tag:blogger.com,1999:blog-56999868214291907052024-03-06T12:02:25.644-08:00Escaping Anergy: The Immunology Research BlogProviding scientific stimulation to fully activate the public's interest in immunology, human health, and disease...one research study at a time.Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.comBlogger13125tag:blogger.com,1999:blog-5699986821429190705.post-73961543211639208012012-02-29T15:12:00.000-08:002012-02-29T15:12:35.162-08:00Ending a (somewhat) Anergic Winter HIbernation...<span style="font-family: Georgia, 'Times New Roman', serif;"><i>Hello Loyal Escaping Anergy Readers!!</i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i><br /></i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i>I am writing to: </i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i>1. thank you all for your continue support of helping to bridge the communication gap between scientists and the public by reading Escaping Anergy: The Immunology Research Blog </i></span><br />
<i style="font-family: Georgia, 'Times New Roman', serif;">and </i><br />
<i style="font-family: Georgia, 'Times New Roman', serif;">2. to explain that I am finally emerging for my Winter Hibernation. Ok so, I wasn't actually burrowed in the ground waiting desperately for the end of cool temperatures, but I was extremely busy with things that tied up my time to sit and write detailed analyses about the latest in amazing immunology research discoveries. What was I doing that consumed all my time? </i><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i><br /></i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i>There was everything from the Holidays and New Years' Celebrations to traveling to California for Research Conference...</i></span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj2kJNOY56aAGfn-KG5JAbbhyMCVhmPonmmslMIgfog_nxke0G7-VArfvy5fry2VC2K0_tWnoJihxN1VJ-XxKNhR1QK_mkuKZNDywZStEnfu-6tDcDE55NOl7ukSWQV_42vpHWUQ9Yr7x0/s1600/IMG_0327.JPG" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj2kJNOY56aAGfn-KG5JAbbhyMCVhmPonmmslMIgfog_nxke0G7-VArfvy5fry2VC2K0_tWnoJihxN1VJ-XxKNhR1QK_mkuKZNDywZStEnfu-6tDcDE55NOl7ukSWQV_42vpHWUQ9Yr7x0/s320/IMG_0327.JPG" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;"><a href="http://www.neaq.org/animals_and_exhibits/animals/sea_dragons/index.php"><span style="color: magenta;">Leafy Seahorse</span></a> seen at the Seahorse Exhibit at the <a href="http://www.montereybayaquarium.org/"><span style="color: magenta;">Monterey Bay Aquarium</span></a> (seen during a very brief break from the conference).</span></td></tr>
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<span style="font-family: Georgia, 'Times New Roman', serif;"><i>to traveling to Jamaica for a wedding and much needed vacation...</i></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKJo5P8TGfGL8k-mkzNsJJ0RQYCSgq1YXOOwFCse_Oxhn9ddWQsZp9-JDZ396HL9jEXrAUYMZ82zWHvS_w4t9Vt-EaTsT6FDiTgtyhJe75IJPJyVOwe7HDUxhHiTFY27tl-HhiLFuGPTU/s1600/_DSC1983.JPG" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="212" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKJo5P8TGfGL8k-mkzNsJJ0RQYCSgq1YXOOwFCse_Oxhn9ddWQsZp9-JDZ396HL9jEXrAUYMZ82zWHvS_w4t9Vt-EaTsT6FDiTgtyhJe75IJPJyVOwe7HDUxhHiTFY27tl-HhiLFuGPTU/s320/_DSC1983.JPG" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">Beautiful Montego Bay, Jamaica!</span></td></tr>
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<span style="font-family: Georgia, 'Times New Roman', serif;"><i>to preparing my own research manuscript for publication to preparing for the start of another semester where I teach a weekly Immunology Discussion section </i></span><i style="font-family: Georgia, 'Times New Roman', serif;">to applying for research grants and fellowships</i><i style="font-family: Georgia, 'Times New Roman', serif;">...</i><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhy6su_xpVnVkDSsX3ebVzA-kGYhf8wPDT4NUcv25RZRjAfDJJ-7YqgZLw_qH8e90_zGgXvxQZz0vybTOZp_jqW3-HMzkG1jhEXu8tGjwBu3aL9WK6Hd1q75g1wmZ3Whxywew4c30Q63_c/s1600/phd101507s.gif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhy6su_xpVnVkDSsX3ebVzA-kGYhf8wPDT4NUcv25RZRjAfDJJ-7YqgZLw_qH8e90_zGgXvxQZz0vybTOZp_jqW3-HMzkG1jhEXu8tGjwBu3aL9WK6Hd1q75g1wmZ3Whxywew4c30Q63_c/s400/phd101507s.gif" width="400" /></a></div>
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<i style="font-family: Georgia, 'Times New Roman', serif;">to beginning to train for a 10-mile race in April...</i><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjW9JLwQSy0kZauJiKykzJGTQ0fdurla0SH49k_iJxtwsndEoDYIN7w-MsBLYJodmlhumfY4_A0IjFsXvXcpuHij0lJSxdw0fP9uxG7gp-DeTrzMBJKOng9Fp9HQ_YggxEtxfdu2QDL70A/s1600/_DSC0193.JPG" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjW9JLwQSy0kZauJiKykzJGTQ0fdurla0SH49k_iJxtwsndEoDYIN7w-MsBLYJodmlhumfY4_A0IjFsXvXcpuHij0lJSxdw0fP9uxG7gp-DeTrzMBJKOng9Fp9HQ_YggxEtxfdu2QDL70A/s320/_DSC0193.JPG" width="251" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">At the end of a half-marathon I ran last season with a few friends, goal this year: 8:30 min/mile for the 10-miler in April!</span></td></tr>
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<i style="font-family: Georgia, 'Times New Roman', serif;"> to expanding our family to include our rescue dog, Ringo!! </i><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhds1vUk9desf8SUHexISgYH6JEjYmIPe0RK_UpawEr8MoK2b9-9UfwYUONwC_ds3FIJB6z5NRCkAmPGxs7yQoDsgWHp1cGFHsTh0C04wZOj2Ndz91chKQYcX2nAYa5F4iFM4CK9WuVczc/s1600/IMG_0345.JPG" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhds1vUk9desf8SUHexISgYH6JEjYmIPe0RK_UpawEr8MoK2b9-9UfwYUONwC_ds3FIJB6z5NRCkAmPGxs7yQoDsgWHp1cGFHsTh0C04wZOj2Ndz91chKQYcX2nAYa5F4iFM4CK9WuVczc/s320/IMG_0345.JPG" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">How could we NOT adopt him?!<i style="font-family: Georgia, 'Times New Roman', serif;"> </i></span></td></tr>
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<span style="font-family: Georgia, 'Times New Roman', serif;"><i>Whew! So, you can say I've been pretty busy lately over these past few months and am happy to report that things are finally quieting down so that I can focus more on Escaping Anergy! </i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i><br /></i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i>Without adding to this blog, does that mean I've been <a href="http://escapinganergy.blogspot.com/2011/05/fighting-disease-by-escaping-anergy.html"><span style="color: magenta;">anergic</span></a> over Winter? Not completely because in addition to responding to your e-mails @ <span style="color: magenta;">escapinganergy@gmail.com</span> and teaching Immunology this semester I have been maintaining a very active Twitter account over these Winter months, so I encourage you to follow me on Twitter to get daily updates about the latest in immunology research! Thank you to everyone currently following @escapinganergy and for your constant support!</i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i><br /></i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i>There has been so much exciting research published in the fields of immunology, human health and disease that I can't wait to write about here. So please stay tuned here at <a href="http://escapinganergy.blogspot.com/"><span style="color: magenta;">Escaping Anergy: The Immunology Research Blog</span></a> and on <a href="https://twitter.com/#!/escapinganergy"><span style="color: magenta;">Twitter @escapinganergy</span></a>! </i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i><br /></i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i>Sincerely,</i></span><br />
<span style="font-family: Georgia, 'Times New Roman', serif;"><i>Heather</i></span><br />
<br />
<br />Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com18tag:blogger.com,1999:blog-5699986821429190705.post-23508466462258407032011-12-05T08:14:00.001-08:002011-12-05T08:40:49.381-08:002011 Blogging Scholarship: Results and THANK YOUs<!--[if gte mso 9]><xml>
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<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: xx-small;">from <a href="http://thecelebrationshoppe.com/"><span class="Apple-style-span" style="color: magenta;">thecelebrationshoppe.com</span></a></span></td></tr>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i>I want to sincerely thank
everyone who voted and helped to spread the word in support of Escaping Anergy
for the 2011 Blogging Scholarship! This year, Escaping Anergy competed against
blogs about the NBA, baseball, religion, shark conservation, paleontology, tech
gadgets and traveling at the chance to win the <a href="http://www.collegescholarships.org/our-scholarships/blogging.htm"><span class="Apple-style-span" style="color: magenta;">2011
Blogging Scholarship</span></a> awarded to full-time students who blog. Being
relatively new to blogging, I was ecstatic to have such amazing support from my
family and friends, The University of Maryland, fellow science bloggers and
science enthusiasts! Although Escaping Anergy lost the ultimate prize (by only
a few hundred votes!) I honestly believe that I wouldn’t have made it as far as
I did without your amazing support! Being able to earn First Runner-Up has
propelled Escaping Anergy into a bigger public arena, which I hope will enable
it to be seen, discussed and further supported by more of the public. The
greatest result of this scholarship adventure has been the chance to advocate
for better public science and health education. Coming in a close second has
revealed that much of the public (at least those who read blogs) craves to have
a more in-depth understanding about the biology behind critical health concerns
and disease. </i></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i><br /></i></span></div>
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<i><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Throughout this scholarship process,
I have received numerous e-mails, <a href="https://twitter.com/#!/escapinganergy"><span class="Apple-style-span" style="color: magenta;">tweets</span></a> and blog posts that not only
positively acclaim the work I’ve done so far on Escaping Anergy, but also have
asked for more information about particular aspects of immunology that may
directly affect their lives. I am genuinely
excited so many people have discovered their interest in immunology through
Escaping Anergy! It was a truly amazing experience to receive so much
positive feedback and messages describing your interest to learn more about
immunology during this process and I hope to continue to hear from you!</span></i></div>
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<i><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">For these reasons, I am so proud
to see Escaping Anergy play a role in enhancing the public’s interest in
immunology! Is there an immunology research paper you found that you’d like to
see further explained? Are you an immunology/med student who has a question as
you prepare for your immunology exam? Is there an immune-based therapy you’d
like to know more about and the research behind it? Did you read a health news
story that mentions the immune system and would like to learn more? I hope you
continue to help spread the word about Escaping Anergy and I look forward to
receiving more e-mails, tweets and posts about how understanding immunology
affects your life and what you would like to see discussed on Escaping Anergy!</span></i></div>
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<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;">Lastly and Very Importantly: an extra special thanks to…<o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><a href="http://www.southernfriedscience.com/"><span class="Apple-style-span" style="color: magenta;">David Shiffman</span></a> and <a href="http://contemplativemammoth.wordpress.com/"><span class="Apple-style-span" style="color: magenta;">Jacquelyn Gill</span></a> who continuously advocated for improved science education as fellow
finalists for the Blogging Scholarship. They are fantastic science bloggers and
I hope with our combined effort, the public has greater appreciation and
support for a variety of scientific issues! A recap of all the science bloggers
who were selected as finalists for the scholarship can be found <a href="http://www.blogger.com/Christie%2520Wilcox,"><span class="Apple-style-span" style="color: magenta;">here</span></a>.<o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;">Christie Wilcox of <a href="http://blogs.scientificamerican.com/science-sushi/2011/11/16/science-bloggers-compete-for-10000/"><span class="Apple-style-span" style="color: magenta;">Science Sushi</span></a> (and winner of the 2010 Blogging Scholarship) who promoted all the
science bloggers up for the 2011 prize and offered generous words and support
for Escaping Anergy on her Scientific American blog:</span></div>
<blockquote class="tr_bq">
<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><b>“<span style="color: #222222;">It’s
not easy to make immunology engaging and interesting, but Heather does a
fantastic job of it. She clearly has a passion for what she does, and loves to
share it with others. She hopes that her blog will help connect the general
public to a field that is often overhyped and misinterpreted – and I’d say
she’s off to a damn good start.”</span></b> </span></blockquote>
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<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;">Mike at <a href="http://www.glutenzap.com/forum/viewtopic.php?f=1&t=3610"><span class="Apple-style-span" style="color: magenta;">GlutenZap.com</span></a> for helping to spread the word and support for Escaping Anergy for the
Blogging Scholarship: </span></div>
<blockquote class="tr_bq">
<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><b>“</b><span style="color: #333333;"><b>I've had the recent pleasure
of exchanging email with Heather Cohen of The Escaping Anergy blog… Folks like
Heather, Her interest in immunology and Her passion about these kinds of issues
are the ones that can make a big difference in finding cures for so many
diseases in my opinion.”</b></span></span></blockquote>
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<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;">Aaron Broege of <a href="http://thesensitivescientist.wordpress.com/2011/11/17/osteoclasts-have-feelings-too/"><span class="Apple-style-span" style="color: magenta;">The Sensitive Scientist</span></a>, who provided constant support for Escaping Anergy
during the scholarship process and did a fantastic job at helping to spread the
word:<o:p></o:p></span></div>
<blockquote class="tr_bq">
<b><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;">"If you like your science served up awesome, vote for Heather's Blog!"</span></b></blockquote>
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<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;">Tom
McCaughtry, fellow immunologist who helped to rally votes and provided constant
support for the need of a blog devoted to immunology research, commenting on PZ
Meyers' post “<a href="http://freethoughtblogs.com/pharyngula/2011/11/21/a-poll-with-a-point/"><span class="Apple-style-span" style="color: magenta;">A
Poll with a Point</span></a>”: </span></div>
<blockquote class="tr_bq">
<b><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;">“<span style="color: #222222;">Heather
Cohen writes an extremely interesting blog that communicates scientific
research to the public. She doesn’t dumb down the science like some of the
other “news” sources, but she makes it simple enough for anybody to
understand!”</span></span></b></blockquote>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><o:p> </o:p><i>Thank you all a million times over,</i></span></div>
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<i><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Heather</span></i></div>
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<!--EndFragment-->Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com10tag:blogger.com,1999:blog-5699986821429190705.post-58364321474066971402011-11-16T07:54:00.001-08:002011-12-04T10:14:56.789-08:00Blogging Scholarship: On the importance of science research blogs and how YOU can vote to support students who blog about science!<blockquote class="tr_bq">
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFqVFVK0zfrs2qrCE_dTsmUg-zJ-9lKIzKxZ8Stn__P4A-OQFzTFu-p77KKD4F0kPWjvcuk7w1pMmPunSj61fcU4mYi1aSIdTNmAPaBD8L928SUbFxDadglSlfVUFnm40BXAS7_zDvIEo/s1600/2011-blogging-scholarship.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="87" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFqVFVK0zfrs2qrCE_dTsmUg-zJ-9lKIzKxZ8Stn__P4A-OQFzTFu-p77KKD4F0kPWjvcuk7w1pMmPunSj61fcU4mYi1aSIdTNmAPaBD8L928SUbFxDadglSlfVUFnm40BXAS7_zDvIEo/s200/2011-blogging-scholarship.jpg" width="200" /></a></div>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span class="Apple-style-span" style="background-color: white; font-size: 12px; line-height: 18px;"><i>"The academic research and teaching communities for science and related fields need to see blogging as more than a casual hobby, as core outreach for their science. It is an effective way for scientists to counter the misunderstandings, deliberate and otherwise, of popular culture...</i></span><span class="Apple-style-span" style="background-color: white; font-size: 12px; line-height: 18px;"><i>In this way, we can ensure that the quality of the science that is communicated to the public is high, while the personality of working scientists humanizes science."</i></span></span> <span class="Apple-style-span" style="background-color: white; font-family: arial, verdana, helvetica, sans-serif; font-size: 12px; line-height: 18px;">-</span><span class="Apple-style-span" style="background-color: white; font-family: Arial, Helvetica, sans-serif; font-size: 11px; line-height: 15px;">John S. Wilkins</span><span class="Apple-style-span" style="font-size: xx-small;"><span class="Apple-style-span" style="background-color: white; font-family: Arial, Helvetica, sans-serif; line-height: 15px;"> "<span class="Apple-style-span" style="color: magenta;"><a href="http://www.sciencedirect.com/science/article/pii/S0169534708002000#sec3"><span class="Apple-style-span" style="color: magenta;">The roles, reasons and restrictions of science blogs</span></a>.</span>" </span><span style="background-color: white; font-family: Arial, Helvetica, sans-serif; font-style: italic; line-height: 15px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px;"> (2008).</span></span></blockquote>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">I started <i>Escaping Anergy</i> because as a PhD Immunology student I wanted to get the public psyched up about the amazing role basic research plays in improving human health! Whether you have supported this blog since its beginning or if you recently stumbled across I hope you find this blog to be <b><span class="Apple-style-span" style="color: magenta;">a unique place on the web where scientists and the public can discuss research and its impacts <i><u>together</u>.</i> </span></b>Your support and interest in <i>Escaping Anergy</i> is what motivated me to apply for a $10,000 scholarship for full-time students who blog and...</span><br />
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="background-color: white;">I JUST found out</span><span style="background-color: white;"> </span><a href="http://www.collegescholarships.org/blog/2011/11/15/2011-blogging-scholarship-finalists/" style="background-color: white;" target="_blank"><span style="color: magenta;"><b>I was selected as a FINALIST</b></span></a><span style="background-color: white;">! However, the winner will be chosen by the online community. Because </span><span style="background-color: white;">my blog is still in its infancy, my chances of winning this scholarship are <b><u>STRONGLY DEPENDENT</u></b> on the great support of my family, friends and fellow science enthusiasts! </span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="background-color: white;"><br /></span></span></div>
<div>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="background-color: white;">Some of the other finalists have been blogging longer than I have and may have more followers on their blogs, so </span><span class="Apple-style-span" style="background-color: magenta;"><b><u>your vote is vital to my chances of winning</u></b>! <b>NOTE: You can only vote once per device, therefore feel free to<u> vote using your work, home computer(s) AND smart phones</u>! Voting ends November 23rd.</b> </span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></div>
<div style="background-color: white;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: large;"><b>Please click <a href="http://www.collegescholarships.org/blog/2011/11/18/2011-blogging-scholarship/"><span style="color: magenta;">here</span></a> to vote for me!</b></span></div>
<div style="background-color: white;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: large;"><b>It only takes a second!</b></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></div>
<div style="background-color: white;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Below is an excerpt from my submitted essay:</span></div>
<div style="background-color: white;">
<blockquote class="tr_bq">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i>" Although I have taught
microbiology and immunology to hundreds of undergrads and launched two
newsletters that are distributed throughout my department to foster
interdisciplinary communication, I yearned to discuss interesting research
discoveries with the public at large. I continue to believe that blogging provides
me with the unique opportunity to do exactly that, while giving me a forum to
improve my writing skills.<br /> I soon began thinking of what kind of blog I would be proud
to write. As an immunologist, I have noticed that although there are ample blogs,
news columns, and television programs conveying general science and health
issues, there wasn’t any public space devoted to discussing basic immunological
research. To fill this important niche, I launched “Escaping Anergy: The
Immunology Research Blog”. Anergy is an immunology term describing the state in
which a T cell is inadequately stimulated and unable to actively participate in
the immune response. Because of this, the anergic T cell is doomed to wander
throughout the body quietly, doing essentially nothing. So how do individuals,
like T cells, become active and prepared to take on whatever health challenges
comes their way? The answer lies in the fundamental basis of my blog: to
provide a second signal called co-stimulation. Co-stimulation refers to the
guiding signal that T cells must receive to strengthen their ability to do all
the things a powerful, active T cell can do. The purpose of my blog is to help
reverse the process of anergy in our community by getting us psyched up about
the biology behind human health issues so that we can become active members of
society and engaged in furthering scientific discovery.<br /> I began this blog out of my genuine interest in both
research and science communication. Although still in its infancy, I feel
empowered with every new visitor who reads my blog, and I believe it is
succeeding as I have received much praise from the online community for my
in-depth analysis of the latest research articles in the fields of immunology,
human health, and disease. I strongly believe that my experience as a blogger
has strengthened my career, my research, my quality of teaching, and perhaps
most importantly, my confidence in my ability to achieve my ultimate goals. I
would be truly honored to receive this award and believe that it will provide
me with significant resources to help publish my research findings, travel to
conferences, attend writing seminars, and ultimately enrich my communication
skills within both the scientific and public communities."</i></span></blockquote>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">I hope you will help advocate science communication and can help spread the word! </span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Thank you for support, it is truly appreciated!</span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Sincerely,</span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Heather</span></div>
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<span class="Apple-style-span" style="font-family: 'trebuchet ms', sans-serif;"><br /></span></div>
<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png" style="border: 0;" /></a></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+ecology+%26+evolution&rft_id=info%3Apmid%2F18597888&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+roles%2C+reasons+and+restrictions+of+science+blogs.&rft.issn=0169-5347&rft.date=2008&rft.volume=23&rft.issue=8&rft.spage=411&rft.epage=3&rft.artnum=&rft.au=Wilkins+JS&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CResearch+%2F+Scholarship%2CCareer%2C+Education%2C+Science+Communication">Wilkins JS (2008). The roles, reasons and restrictions of science blogs. <span style="font-style: italic;">Trends in ecology & evolution, 23</span> (8), 411-3 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/18597888" rev="review"><span class="Apple-style-span" style="color: magenta;">18597888</span></a></span>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com13tag:blogger.com,1999:blog-5699986821429190705.post-29309189826701064702011-10-27T14:46:00.000-07:002011-11-02T20:52:51.224-07:00Discussion Forum: How Dogma Hinders the Advancement of Basic Research<br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFxBW-kgoMxPS7pZBsIdk1vjZa5Pk1Q4aepA6cyY3BS0Y9F7mHLooWr99TqU6VHzu4lqOsg6xTR55TAawPKgFPk2d80ZqmHqbQVlw9BOXMHnRA__c3uM6qWYg-0zyPmo5SBRq2HbilJV8/s1600/produktbilde_central_dogma.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="212" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFxBW-kgoMxPS7pZBsIdk1vjZa5Pk1Q4aepA6cyY3BS0Y9F7mHLooWr99TqU6VHzu4lqOsg6xTR55TAawPKgFPk2d80ZqmHqbQVlw9BOXMHnRA__c3uM6qWYg-0zyPmo5SBRq2HbilJV8/s320/produktbilde_central_dogma.jpg" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: xx-small;">from <a href="http://okapi.berkeley.edu/public-research/?p=397#comment-975"><span class="Apple-style-span" style="color: black;">Dissemination of Research</span></a></span></td></tr>
</tbody></table>
<span class="Apple-style-span" style="font-family: Arial;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">There is so much
interesting aspects to the field of immunology in addition to the amazing
research it offers, including historical and societal issues, that perhaps if
discussed candidly would increase the public’s support and value towards basic
research. In addition to writing
and discussing the latest published research in the fields of immunology,
disease and human health, I would like to experiment with a few other forums to
present on <b><span class="Apple-style-span" style="color: magenta;">Escaping Anergy</span></b>. This is the first installment of <b><i>Discussion
Forum</i></b> devoted to enhancing our ability to discuss immunology in
an open, philosophical, communicative way. After all… <o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Immunology is complicated.
It’s like a giant puzzle without a box depicting how the picture is
supposed to look. It becomes
further complicated, because every few years a new puzzle piece drops into the
pile. The thing is, sometimes it
feels as Sometimes that new piece in the “missing link” that can unify part of
the puzzle, and other times it can’t seem to fit into the existing puzzle. In research, the puzzle, in its
entirety, is never complete, but people are working towards completing smaller
chunks of the puzzle that can explain major biological processes. Dogma represents a big chunk of the
puzzle completed, but that can’t incorporate the remaining puzzle pieces. It is much easier to accept the idea
that at least a portion of the puzzle is completed, than to re-examine the puzzle to ensure that the all the pieces in the completed
section fit together smoothly and not forced into curves. Fortunately, there are a number of scientists and educators who never lost their ability to question and whose curiosity has not waned. </span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> Taking
a few moments to describe how current dogmas evolve, one can begin to
appreciate the challenges scientists encounter when trying to understand
biological phenomena. For example,
in my specific field, macrophage biology, the dogma describing the function of
these cells, has been under constant revision since their discovery at the turn
of the 20<sup>th</sup> century. In the late 1890’s, <a href="http://en.wikipedia.org/wiki/Elie_Metchnikoff"><span class="Apple-style-span" style="color: magenta;">Elie
Metchnikoff</span></a> (the “<a href="http://onlinelibrary.wiley.com/doi/10.1002/eji.200838855/pdf"><span class="Apple-style-span" style="color: magenta;">Father of
Natural Immunity</span></a>”) first described these cells merely based on what he
could physically see: big tissue cells that were able to rapidly engulf dead
cells. For these reasons, he aptly
called them “macrophages”. <sup>1</sup> Over the next 60 years, scientists
around the world wanted to know more about what role these “big eaters” have in
the immune system. In the mid-20<sup>th</sup>
century, a sentinel experiment by Mackaness and colleagues was performed using bacteria-infected
macrophages. <sup>2</sup> In these experiments, they analyzed what the
macrophages produced during infection and discovered that not only were these
cells very good at eating and destroying bacteria, but produced huge amounts of
pro-inflammatory cytokines as well.
These cytokines,
TNFalpha and IL-12, are crucial mediators of the adaptive immune response and
cellular recruitment to the site of infection. This inflammatory, anti-microbial phenotype was then used to describe macrophage function for nearly 50 years. Immunologists</span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> were largely content with relying on this new dogma of "classical macrophage activation". </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">This compelling description of macrophage function seemed to be etched into stone for decades, being unequivocally taught to future immunologists and so on. It would be nearly half a century would pass before anyone proposed the notion of "alternatively activated macrophages". This, to me, seems a bit surprising, after all </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">in a field where people are
trained to question their surroundings, be curious and ask questions, the idea
of accepting dogma and moving on, should struggle to persist. </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> Before the millennium was over,
numerous groups had discovered alternative activation macrophage states,
including macrophages that were exactly the opposite of Mackaness’ classical
macrophages.</span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Siamon Gordon, David
Mosser and others discovered all sorts of abilities macrophages possessed that were
previously thought of as impossible.</span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">
</span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">They had described macrophages that although were still very good at
phagocytosis, were not able to control microbial infections and macrophages
that were potent anti-inflammatory cytokine producers playing a significant
role in regulating inflammation.</span><sup style="font-family: Georgia, 'Times New Roman', serif;">3,4 </sup><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><b style="background-color: white; font-family: Georgia, 'Times New Roman', serif;"><span class="Apple-style-span" style="color: magenta;"><u>Finally,</u> we are beginning to appreciate
that our previous understanding of macrophage function was over simplified and
restricted; in fact we know believe there is a whole spectrum of macrophage
diversity to explain how these cells work, behave and modulate immune
responses. </span></b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">It turns out that
macrophage are capable of behaving in so many different ways depending on what
they sense in their environment, and when and under what conditions.</span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">However what factors regulate
macrophage function and how and importantly, what other functions are these
cells able to perform remain incomplete and elusive. It is stunning to imagine what discoveries could have been made sooner if not for the 50-year lag in providing evidence for such an array macrophage activation states. <span class="Apple-style-span" style="color: magenta;"><b>It is now known that such alternatively activated macrophages play significant roles in tumor development, microbial susceptibility, intestinal homeostasis and wound healing!</b></span></span><br />
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">I believe that it is this fast-paced, dramatic evolution of understanding
that provides the mystique that attracts people to the field, while
simultaneously representing a major driving force to discourage people from
taking an interest in research. However, the puzzle of understanding biological
depends on the public’s support of basic research, which tackles essential
questions that must be answered or expanded upon, in order to fully understand
the mechanism behind disease.<o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">As
a doctorate student, I am supposed to devote most of my waking (and often,
dreaming) hours to my research thesis, if I ever hope to successfully complete
my PhD and move on to future endeavors.
Although, my time in the lab consumes 95-98% of the hours in a week, I
desperately savor a few hours each week to “break” from the bench and take time
to learn something new about immunology.
I treasure this time because, with all my course-work completed, I still
yearn to learn new things. I use
this time to stay current with new discoveries and ideas and to further educate
myself in immunology. The time I
spend reading the latest published research reminds me why I began
investigating scientific research as a career in the first place: to always be
in a position to challenge myself to learn new things. <b><span class="Apple-style-span" style="color: magenta;">The field of immunological research is very challenging largely,
because what we [think] we know about it is always morphing and expanding, new
discoveries are always being made, and models of understanding are always in
revision.</span><o:p></o:p></b></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">I
understand this is exactly the aspect of science that often discourages people
from wanting to learn more about it or why so many educators resort to using
test-books that lump together decades of research to create main bullet points
of understanding for students to memorize as facts. But I think if we want <b><span class="Apple-style-span" style="color: magenta;">to
advance our scientific understanding of disease, we must be able to effectively
and openly discuss how new research findings supports or changes current understanding</span></b>. </span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">All children are curious beings,
constantly trying to figure out the world around them and how it works. Somewhere along the path to adulthood
most of us, abandon our ability to do this. We figure it’s easier to live in a world where other people
figure things out; after-all our lives have become increasingly more hectic
since we were kids. <b><span class="Apple-style-span" style="color: magenta;">For science to
work the way we want it to-by providing insight into how our bodies work so
that we can cure, prevent, and effectively treat diseases, all of us-scientists
and non-scientists-must continue to think creatively and intelligently about
the amazing physiological phenomena our bodies encounter everyday. </span></b></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><o:p></o:p>Biological research is a very challenging field with limited immediate satisfaction. These qualities tend to push the vast majority of would-be scientists away from the realm of research. By assuming our current understanding of immunology is static and somehow set in stone, the field is doomed to lend itself in the development of drugs and treatments that work effectively and properly to treat disease. </span></div>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">
</span><br />
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Whether
you are also a young scientist, or an older one, or someone who just wants to
make more time in their busy life to learn something new, or a concerned
citizen who wants to understand how their tax dollars lead to scientific
advancement, I encourage you to ask more questions and to never take the easy
route to scientific understanding!
Thanks for reading and I hope our discussion continues!</span><span class="Apple-style-span" style="font-family: Arial;"><o:p></o:p></span></div>
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<b><span class="Apple-style-span" style="color: magenta; font-family: Georgia, 'Times New Roman', serif;">What makes you want to
understand immunology and support the research behind it? <o:p></o:p></span></b></div>
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<b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span class="Apple-style-span" style="color: magenta;">What motivates you to
continue to be curious about science?
</span><o:p></o:p></span></b></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Please feel free to comment below or shoot me an e-mail to discuss the philosophy of immunological research!</span></div>
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<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_white.png" style="border: 0;" /></a></span><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+Reviews+Immunology&rft_id=info%3Adoi%2F10.1038%2Fnri2448&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Exploring+the+full+spectrum+of+macrophage+activation&rft.issn=1474-1733&rft.date=2008&rft.volume=8&rft.issue=12&rft.spage=958&rft.epage=969&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fnri2448&rft.au=Mosser%2C+D.&rft.au=Edwards%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CPhilosophy%2CResearch+%2F+Scholarship%2CImmunology%2C+Philosophy+of+Science%2C+Science+Communication">Mosser, D., & Edwards, J. (2008). Exploring the full spectrum of macrophage activation <span style="font-style: italic;">Nature Reviews Immunology, 8</span> (12), 958-969 DOI: <a href="http://dx.doi.org/10.1038/nri2448" rev="review"><span class="Apple-style-span" style="color: magenta;">10.1038/nri2448</span></a></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"><b><i><u><br /></u></i></b></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"><b><i><u><br /></u></i></b></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"><b><i><u><br /></u></i></b></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"><b><i><u>References and Further
Reading:</u></i></b><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">1:<span class="apple-style-span"><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial;"> </span></span>Metschnikoff,
E. <i>Biol. Zentralblatt</i> <b>3</b>: 560–565 (1883).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">2: Mackaness, G. B. "<a href="http://www.ncbi.nlm.nih.gov/pubmed/14194388?dopt=Abstract&holding=npg"><span class="Apple-style-span" style="color: magenta;">The
immunological basis of acquired cellular resistance. </span></a>"<i>J. Exp. Med.</i> <b>120</b>:105-120(1964).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">3: Stein, M., Keshav, S., Harris, N. & Gordon, S. “<a href="http://jem.rupress.org/content/176/1/287.abstract"><span class="Apple-style-span" style="color: magenta;">Interleukin 4 potently
enhances murine macrophage mannose receptor activity: a marker of alternative
immunologic macrophage activation</span></a>”. <i>J. Exp. Med.</i> <b>176</b>:
287–292 (1992).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">4: Mosser, D. and Edwards, J. “<a href="http://www.nature.com/nri/journal/v8/n12/full/nri2448.html"><span class="Apple-style-span" style="color: magenta;">Exploring the
full spectrum of macrophage activation</span></a>”. <i>Nature Reviews Immunology</i>. <b>8</b>:958-969.
(2008).</span><span style="font-size: 10pt;"><o:p></o:p></span></div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com13tag:blogger.com,1999:blog-5699986821429190705.post-50976632180608761492011-10-10T13:28:00.000-07:002011-11-13T16:46:06.221-08:00Silencing "The Silent Killer": Researchers reveal promising new strategy to prevent and diagnose osteoporosis<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgxO_Eoe0JVVkl3txF-HlB479Bn8PO1CYAcI1m_SM5MtTa5gqYMiHFwH3zl3SU80eSqhpp7f90NDVNOLUViowBktmSaVTHby_KJa75Zhov-GHjpA60BoXLS778imgLzP5sKPt7trgingRw/s1600/bone11.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="288" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgxO_Eoe0JVVkl3txF-HlB479Bn8PO1CYAcI1m_SM5MtTa5gqYMiHFwH3zl3SU80eSqhpp7f90NDVNOLUViowBktmSaVTHby_KJa75Zhov-GHjpA60BoXLS778imgLzP5sKPt7trgingRw/s400/bone11.png" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Healthy bone structure (left) vs Osteoporotic bone (right). <span class="Apple-style-span" style="font-size: xx-small;">From <span class="Apple-style-span" style="color: magenta;">www.karger.com</span></span></span></td></tr>
</tbody></table>
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<b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i><u>Public Interest Note:</u></i><o:p></o:p></span></b></div>
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<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> Put two simple, innocuous words together
and you get a longer word describing a disease that affects 200 million women
worldwide: <span style="color: black;">“Osteo”</span> from the Greek word “osteon” meaning “bone” and <span style="color: black;">“Porosis” meaning
porous. Porous bones. Bone filled with cavities. Bone loss. Weak bones. Fractured bones. These phrases simply describe what
having osteoporosis means.<o:p></o:p></span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="color: black;"> With
such simplicity in describing the biological effects of this disease, it’s
surprising that much of the public need celebrities</span> like Sally Field to describe the importance of bone health to the
public. However, with an estimated
<a href="http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/osteoporosis-disease/"><span class="Apple-style-span" style="color: magenta;">54%
of postmenopausal women being osteopenic (lower than normal bone mass) and 30%
exhibiting full-blown osteoporosis,</span></a> the bone health industry and advocates for
promoting bone health are trying everything they can think of to get people to
pay attention this “silent killer”.<o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> Hold
up! Did I just go from the Greek word
for “bone” to “killer” in just
over 100 words? Unfortunately,
it’s that easy to connect these two seemingly disparate terms. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Osteoporosis
is often called “<a href="http://news.bbc.co.uk/2/hi/health/5198628.stm"><span class="Apple-style-span" style="color: magenta;">the
silent killer</span></a>” because individuals who have the disease are usually unaware
that they have it until a bone fractures.
Serious bone fractures often leave individuals with osteoporosis
debilitated and can enhance susceptibility to infectious diseases, which can
result in death. In fact, according
the International Osteoporosis Foundation, women over the age of 50 have “a
2.8% risk of death related to hip fracture…equivalent to her risk of death from
breast cancer and 4 times higher than that from endometrial cancer”. Importantly,
the occurrence of bone loss is not limited to having two X chromosomes, as <a href="http://www.iofbonehealth.org/facts-and-statistics.html" style="font-weight: bold;"><span class="Apple-style-span" style="color: magenta;">men over the age 50 have a 30% risk of experiencing an osteoporotic fracture,similar to the risk developing prostate cancer.</span></a><b><o:p></o:p></b></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span class="Apple-style-span" style="color: black;">National
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) recommends
that people </span><b><a href="http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/osteoporosis_ff.asp"><span class="Apple-style-span" style="color: magenta;">“consider to talk to [their] doctor about osteoporosis” if you have broken a bone and are over the age of 45 (regardless of sex), if you are a 65+ year old woman, are taking certain medications that are known to cause bone loss,have developed poor posture, if you are a woman whose menstrual periods have stopped (or never started upon puberty), if you have anorexia, or have a chronic illness that is known to contribute to bone loss. </span></a></b> In most of these cases however,
individuals at risk do not think of consulting their doctor until symptoms
start to appear. Scratch that.
Symptom starts to appear. <b><span class="Apple-style-span" style="color: magenta;">The major symptom of osteoporosis is
experiencing a bone fracture, which at that point the disease is so progressive
that prevention of the disease no longer applies.</span> </b> Furthermore, treatments may not be able to reverse the level
of bone lost at this late stage in disease development, increasing the chance
of repetitive bone fractures and risk of death in the future.<b><o:p></o:p></b></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">In
addition to the need for more effective therapies on the market to treat
osteoporosis, there are currently a limiting number of diagnostic tools that
can be easily utilized in the clinic.
Currently, the main tests to assess a person for bone loss is to analyze
his or her bone mineral density (BMD), bone strength, and bone turnover. However, there are limitations to
current diagnostic strategies including correlating data obtained from varying
instruments, bone used for density and strength tests are not always uniform
between testing clinics and techniques used, and in the case of assessing bone
turnover in the blood and urine, these tests do not confidently correlate with
disease progression. <b><span class="Apple-style-span" style="color: magenta;">Therefore in order to treat this disease
effectively, the need for more precise diagnostics is urgent.</span></b><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Notably,
the loss of bone strength does not only inflict men and women with hormone
imbalances, but is also caused by various drugs like glucocorticoids and
chronic illnesses such as rheumatoid arthritis, periodontitis and cancer. Additionally, bone loss has been
observed in individuals who live with little to no bone mobilization as seen in
individuals who are confined to a bed and in astronauts who live for long
periods of time in zero-gravity environments.</span><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Bone
loss is becoming of greater importance to confront as a society as large
portion of our population ages into their 50s and beyond. Serious bone fractures can lead to chronic
pain, reduced mobility, disability and an increasing degree of dependence,
which not only negatively impacts our Nation’s workforce, but forcing the
public to pay millions of dollars annually to cover bone-fracture-related
costs. <b><span class="Apple-style-span" style="color: magenta;">In 2005, it was estimated that over 2 million fractures were treated
costing $17 billion in healthcare costs.
<a href="http://www.blogger.com/2%20million%20fractures%20were%20treated%20costing%20$17%20billion%20in%20healthcare%20costs.%20%20The"><span class="Apple-style-span" style="color: magenta;">The
International Osteoporosis Foundation</span></a> predicts the incidence rate to
increase by 50% in 2025, costing upwards of $25 billion to cover medical
treatments in the U.S. </span></b><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Whether
you care most about the pain people with osteoporosis endure, the deficiency of
effective, accurate diagnostics, or the dismal economics associated with the
disease, the scientists studying the disease need the public’s continuous
support. With such support,
researchers will continue to enhance our understanding of the disease, discover
new drug targets and design novel therapeutics to turn the trend of this
debilitating disease around.<o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> <o:p></o:p></span></div>
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<b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i><u>Our Bones and Our Immune System I: How Our Immune
System Relies on Our Bones</u></i><o:p></o:p></span></b></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHESgQWs0V4aex1ZCqpvKmT1p97D5hPDAu2PhBlHRmzGSwDF6uMSO1VYJ-Zg_A8jtcVcpLek0mquduVMdHkH2HgN4E1VONdxnrqZTvHjfKfGj_wsSdA-dsmtsI-ayguekvawgESlPJ-O8/s1600/bone2.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="348" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHESgQWs0V4aex1ZCqpvKmT1p97D5hPDAu2PhBlHRmzGSwDF6uMSO1VYJ-Zg_A8jtcVcpLek0mquduVMdHkH2HgN4E1VONdxnrqZTvHjfKfGj_wsSdA-dsmtsI-ayguekvawgESlPJ-O8/s640/bone2.png" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Immune cell development occurs primarily in the bone marrow before cells. <span class="Apple-style-span" style="font-size: xx-small;">From <a href="http://www.ihtc.org/"><span class="Apple-style-span" style="color: magenta;">www.ihtc.org</span></a></span></span></td></tr>
</tbody></table>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> The
first thing that students in an Immunology 101 course learn is a process called
hematopoiesis. <b><u style="background-color: magenta;">Hematopoiesis</u></b> is a unnecessarily big
word to describe how a stem cell becomes an immune cell. It makes sense to start a course with
learning this concept, however, it is usually briefly described and skimmed
over by the lecturer. Perhaps it
is because most students are more interested in learning about things that they
have heard of before like: antibody production, organ/tissue donation,
infection, cancer and vaccine development. At any rate, hematopoiesis probably represents
about 1% of the material students will learn about immunology-which is
unfortunate, because there is a lot of amazing things happening when an immune
cell is “born”, that we need more research done to fully understand it all!<o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">So,
if we had to pick somewhere in the body for an immune cell to be born, we might
think of the lymph nodes, spleen or the blood; after all these are the most
popular organs associated with immune function, right? However, surprisingly, the site where
hematopoiesis occurs-where immune cells develop and mature is in the bone. The bone marrow is where all immune
cells, except T cells, spend all their time until they migrate throughout our
blood and tissue ready to protect us from infection and injury. In fact, the “B” in B cell comes from <span class="apple-style-span"><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; color: black;">bursa of Fabricius</span></span><span class="apple-converted-space"><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; color: black;">, which was discovered in the late 1950’s
as the organ where antibody-producing cells developed (compared to the
thymic-derived T cells, hence what the “T” in T cell means). If you are wondering why the “B” stands
for some organ you probably have never heard of and not “bone marrow”, it is
because those original 1950’s experiments were performed on birds, and a decade
later it was discovered that mammals don’t have a bursa of Fabricius, but is
analogous to mammalian bone marrow.</span></span></span><span class="apple-converted-space" style="font-family: Georgia, 'Times New Roman', serif;"><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; color: black;"> <sup>1</sup> </span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">From
birth to their “adolescence” most of our immune cells are intricately connected
to the bone environment. Since
this revelation, much research has unveiled important factors of hematopoiesis and
the mechanisms that explain how cells emigrate from the bone into tissue. In addition, it is known the bone
environment is a critical component of maintaining a constant supply of immune
cell populations, which is important to clear infections as well as reconstituting
the an immune system after exposure to radiation and chemotherapies. With
over 60 years of research in hematopoiesis, the medical field has greatly
benefited from our understanding of how bone impacts immune cell
development.<span style="font-weight: bold;"> </span><span class="Apple-style-span" style="color: magenta;"><b>However, over this
same period, little research has been devoted to understanding the other aspect
of this bone-immune cell relationship: </b><i style="font-weight: bold;"><u>how
immune cells impact to bone development and health</u></i></span><b><span class="Apple-style-span" style="color: magenta;">.</span><o:p></o:p></b></span></div>
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<b><i><u><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></u></i></b></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><b><i><u>Our Bones and Our Immune System II: How Our Bones
Rely on Our Immune System</u></i><o:p></o:p></b></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEib8apkCZRiKuMSMviTpKUx9-rLVeFXOAUs0Kg_SWjwJ5RdnKnNGQFwzL-kPusivkALhKsIXf15kO-UYeK5j_rcgSNL-JAYs4CqDKWArJ72CZuYLvMnHJK_cZHfE5K3h9WSlDNuAvZSZtU/s1600/Untitled.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEib8apkCZRiKuMSMviTpKUx9-rLVeFXOAUs0Kg_SWjwJ5RdnKnNGQFwzL-kPusivkALhKsIXf15kO-UYeK5j_rcgSNL-JAYs4CqDKWArJ72CZuYLvMnHJK_cZHfE5K3h9WSlDNuAvZSZtU/s400/Untitled.png" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> Cytokines associated with the chronic inflammatory disease, rheumatoid arthritis are used to model the complex nature of the immune system regulating bone development.</span> <span class="Apple-style-span" style="font-size: xx-small;">From <a href="http://www.rndsystems.com/BioBrief_2009i1.aspx"><span class="Apple-style-span" style="color: magenta;">R&D.com</span></a></span></td></tr>
</tbody></table>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">The
idea that immune cells impact bone development seemed to happen serendipitously
in the 1990’s, beginning with the discovery that one of the major cell types
that make up our bones was derived from a hemopoetic cell. Soon, Udagawa and colleagues published their
research findings that monoytes can turn into bone cells called <b><u style="background-color: magenta;">osteoclasts.</u></b><o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> <b><u style="background-color: magenta;">Monocytes</u></b>
are unique immune cells because unlike B cells, for example, which will always
be B cells, monocytes can further differentiate into a variety of immune
cells. Monocytes are able to do
this because they are acutely sensitive to changes in their microenvironment
and highly responsive to a range of stimuli that instructs the monocyte to turn
into a different kind of cell.
Osteoclasts, macrophages, dendritic cells, and microglial cells all
derive from a monocyte precursor.
What makes each of these cells unique is what stimuli a monocyte
senses. For example, in vitro, to
generate macrophages (which I do on a weekly basis), all you need to do is
isolate bone-marrow cells or monocytes and throw in some macrophage-colony
stimulator factor (M-CSF), wait a week and you’ve got macrophages! If you want dendritic cells, do the
same thing, but this time in addition to M-CSF add some IL-4. Back when it was just learned that
osteoclasts come from monocytes, a lot of research was done to figure out two
major things: 1) what exactly an osteoclast was and 2) what a monocyte needed
to become a bone cell. </span><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><o:p></o:p></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">An
osteoclast is a macrophage-like cell.
This seems to be post heavy with Greek terminology, so I’ll keep it up
by describing a macrophage as a cell that is very big (aka “macro”). An osteoclast is very similar in that
they too are huge, in fact they are often referred to as (and I am not making
this up): “giant cells”. They are
so big because are created when developing monocytes fuse into a single, giant
cell. One of the most
distinguishing traits of an osteoclast is that they are multi-nucleated. Osteoclasts differ from macrophages in
many ways; however, including first and foremost-they stick specifically to
bone instead of residing in tissue.
Moreover, unlike other monocyte-derived cells, osteoclasts are capable
of <b><span class="Apple-style-span" style="color: magenta;">resorption</span></b>, the process of
degrading bone by pumping large amounts of hydrogen ions into the bone. Accumulation of these ions and other
enzymes from the osteoclast into the bone causes the bone matrix to acidify and
break down, which results in cavities in the bone. Cavities typically have a negative feeling associated with
them, but destruction of bone is not always a bad thing. Think of what would happen if
your bones just kept growing. You
might develop strange bone abnormalities or have problems acquiring enough
nutrients to keep the excess of bone healthy. So bone development, like everything in biology is a tightly
regulated process. In order to understand
how errs in bone development lead to osteoporosis, it is important to
appreciate how osteoclasts are generated, as they are the key to the pathology
associated with bone disease. </span><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Firstly,
what a monocyte needed to turn into an osteoclast proved to be more complicated
than anticipated. Initially it was
difficult because there were two groups of researchers working separately on
something that unbeknownst to them at the time, was in fact the same
thing. There were the people
studying bone trying to figure out more about how bone developed and there were
the people working on the immune system trying to figure out how monocytes
turned into osteoclasts. For
example, in the 1990’s, two important discoveries were made: First, the bone
physiologists identified a protein, expressed by osteoblasts and stromal cells
that was proven to be essential to osteoclast development- they called this
protein osteoclast differentiation factor (ODF). Secondly, the immunologists were please to announce the
discovery of receptor activator of nuclear factor kappa-B ligand (<b><span class="Apple-style-span" style="color: magenta;">RANKL</span></b>), which is produced by T cells
and was determined to be the second stimulus, in addition to M-CSF a monocyte
needs to turn into an osteoclast.
It was later revealed that both groups of researches had actually
discovered the same protein such that ODF is identical to RANKL! <sup>2</sup> Realizing this, Drs. Joseph
R. Arron and Yongwon Cho quickly coined the term ‘<b><span class="Apple-style-span" style="color: magenta;">osteoimmunology</span>’</b> to be “used to describe the interface between
these two disciplines”. The authors
of the article go on to explain, “Without a better understanding of this
interface, it will be difficult to prevent or treat many common diseases that
affect both bones and the immune system”. <sup>3</sup><o:p></o:p></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><sup><br /></sup></span><br />
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<b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i><u>Treatments for Osteoporosis: Why this research
matters:<o:p></o:p></u></i></span></b><br />
<b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i><u><br /></u></i></span></b><br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgkpR7xjhgmnWIbBLsrqPEvms16a7a1X8saSgogVoK8GjPQFOcKimEXuKQ3_7QqMDqHjkdgVSCDB8N0FMog8yP-KLES87YC9_1xsgtpqNrQSEF_rbDUY4mtxgRPLmcv1uxEoEnRIwsfZ-0/s1600/proj_osteogrowth_USSG.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgkpR7xjhgmnWIbBLsrqPEvms16a7a1X8saSgogVoK8GjPQFOcKimEXuKQ3_7QqMDqHjkdgVSCDB8N0FMog8yP-KLES87YC9_1xsgtpqNrQSEF_rbDUY4mtxgRPLmcv1uxEoEnRIwsfZ-0/s400/proj_osteogrowth_USSG.jpg" width="310" /></a></div>
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<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Bones
are “Often thought of as a rigid, unchanging entity, skeletal bone is actually
the result of a dynamic process” involving a balancing act between the activity
of bone formation by osteoblasts and
bone destruction by osteoclasts.
The harmony between these two processes is essential for maintaining
strong bones. <span class="Apple-style-span" style="color: magenta; font-weight: bold;">It is when the rate of bone resorption exceeds the rate of bone
formation that leads to osteoporosis.</span><span style="font-weight: bold;"> </span>Why does this happen? How can we slow the rate of
resorption? What factors are present that promote osteoclast function to
degrade bone? If we knew the answers to these questions we could better treat
bone-loss related diseases or prevent the incidence of bone fractures! <o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">The
“gold standard” for osteoporosis therapy is the use of bisphosphonates, which
first entered the drug market in the late 1990’s by Merck [Fosamax aka
alendronic acid] and Sonofi-Aventis/Proctor and Gamble [Actonel aka risedronic
acid]. Currently drugs that are
classified as bisphosphonates to treat bone loss represent more than 70% of the
market with the expansion of generics and drugs that have improved dosage like
Boniva [<span style="color: #1f1e21;">zoledronic acid, Novartis]. Another</span> big reason for dominance of these drugs in the market is the history of
50 years of research detailing how how bisphosphonates regulate bone
development. <sup>4</sup></span><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><o:p></o:p></span><br />
<div class="separator" style="clear: both; text-align: center;">
</div>
</div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">So
what are bisphosphonates and how do they work? They are simple, small chemicals that consist of two
phosphonate groups (PO3-) linked together by a carbon atom. These chemicals are particularly good
at binding to calcium, so when they enter the body, bisphosphonates concentrate
in the bone. Drugs in the
bisphosphonate class decrease bone resporption because once they enter a cell,
they inhibit the cell’s ability to metabolize energy (ATP), which leads to a process
called apoptosis or cell death.
Because osteoclasts are intimately bound to bone and have some
macrophage-like properties like gobbling things up, bisphosphonates are
particularly good at killing osteoclasts, thereby reducing bone resorption.<sup>
5</sup> <o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">However,
to no surprise, there are multiple risks and side effects associated with this
class of drugs including: gastrointestinal irritation, oeophageal irritation,
hypocalcaemia, renal irritation or more rarely: osteonecrosis of the jaw and
atrial fibrillation. There many
reasons why there is a need for newer drugs on the osteoporosis market. For one thing, bisphosphonates and
other available drugs are not very specific to osteoclasts. Any cell has the potential to take up a
small chemical and be affected by it.
In addition, although the majority of the drug will work at its target
site (bone), some amount of the drug is likely to influence the function of
off-target sites as well.
Furthermore, these small chemicals are given orally introducing a high rate
of non-compliance by patients, decreasing the potential efficacy of the drug.<sup>
4</sup><o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Second
to bisphophonates in populatrity is a class of drugs called selective estrogen
receptor modulators (SERMs).<sup> 4</sup> Although a decrease in estrogen tends to correlate with
the onset of osteoporosis, which one reason why the prevalence of this disease
is greater in post-menapausal women, there are a variety of reasons why SERMs
are not the most effective treatment for bone loss. For one, estrogen is not the only factor influencing the
development of osteoporosis, and does not correlate in every case. It is difficult to determine what, if
any, is the threshold for estrogen that a women should have to prevent
bone-loss. Furthermore, SERMs are
not as effective for women with sufficient estrogen levels or men that suffer
from the disease.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Over
the last few decades there has been strong developments made to generate drugs
that have increased specificity, direction towards the target site, and
effectiveness. Furthermore, there
is a great desire to not only treat bone loss, but to develop better diagnostic
tools to diagnose bone loss, before the disease triggers a debilitating
fracture. According to a recent review regarding the osteoporosis drug
pipeline, “the osteoporosis market has not been a major target for
innovation. R&D activities are
targeted at improving existing dosing regimens with the goal of reducing the
pill burden in a highly medicated population”. At the top of the list for
innovative, promising treatments for osteoporosis is an immunotherapy drug
called <a href="http://www.amgen.com/media/media_pr_detail.jsp?year=2011&releaseID=1607920"><span class="Apple-style-span" style="color: magenta;">Denosumab
(Brand name(s): Prolia<sup>®</sup>,<sup> </sup>Xgeva<sup>®</sup>). </span></a> Denosumab is an antibody that binds
tightly to RANKL. Denosumab is
classified a <b style="background-color: magenta;"><u>blocking or
neutralizing antibody</u></b> because when it binds to its target, it attaches to
the target very specifically and very tightly, blocking the function of the
target. Denosumab, binds tightly
to RANKL, preventing RANK from activating it. Because of this, the side effects can be potentially
very limited, compared to chemical inhibitory drugs.<sup> 6</sup> Furthermore, because it is injected
subcutaneously 1-2/year it enhances patient compliance since patients would not
be required to remember to take oral pills, like for bisphosphonates. Moreover, in mice it has been shown to
inhibit osteoclast development and bone resorption. <a href="http://www.cancer.gov/cancertopics/druginfo/fda-denosumab"><span class="Apple-style-span" style="color: magenta;">Just last
month, Denosumab received U.S. FDA approval for human use to treat bone loss in
patients with breast and nonmetastatic prostate cancer.</span></a> It is currently in clinical trials
expand its use to other osteoporotic diseases. Amgen is developing Denosumab.</span><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">In
order to enhance the number of promising therapies in the R&D pipeline,
more research focusing on the basic immunological understanding of the disease is
needed. By fully understanding the biological mechanisms behind disease
development, we can then develop innovative, effective therapies and diagnostic
tools to help answer these questions:<o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></div>
<div class="MsoListParagraphCxSpFirst" style="margin-left: 1.0in; mso-add-space: auto; mso-list: l2 level1 lfo1; text-indent: -.25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">·<span style="font: normal normal normal 7pt/normal 'Times New Roman';">
</span>Is there a way
to not only delay the onset of disease, but also prevent it? <o:p></o:p></span></div>
<div class="MsoListParagraphCxSpMiddle" style="margin-left: 1.0in; mso-add-space: auto; mso-list: l2 level1 lfo1; text-indent: -.25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">·<span style="font: normal normal normal 7pt/normal 'Times New Roman';">
</span>Is there a way
to not only reduce the chance of bone fracture, but to prevent it? <o:p></o:p></span></div>
<div class="MsoListParagraphCxSpLast" style="margin-left: 1.0in; mso-add-space: auto; mso-list: l2 level1 lfo1; text-indent: -.25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">·<span style="font: normal normal normal 7pt/normal 'Times New Roman';">
</span>Is there a way
to improve our method of detecting disease, as individuals with slightly low
bone mass may go under-the-radar of current bone density measurements?<o:p></o:p></span></div>
<div class="MsoListParagraphCxSpLast" style="margin-left: 1.0in; mso-add-space: auto; mso-list: l2 level1 lfo1; text-indent: -.25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></div>
<b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Without promoting our understanding of how disease develops, we are stuck, unable to move forward in a world where we have safe, available therapies to treat, cure and prevent diseases like osteoporosis</span></b><br />
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><i><u>What the &*%$#! Does the Title Mean?!</u></i><o:p></o:p></span></b></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Hsu, YH., et al. “<b><a href="http://jem.rupress.org/content/early/2011/08/10/jem.20102234.full"><span class="Apple-style-span" style="color: magenta;">Anti-IL-20
monoclonal antibody inhibits the differentiation of osteoclasts and protects
against osteoporotic bone loss</span></a></b>”.
<i>Journal of Experimental Medicine</i>.
208:1849-1861. (2011).<o:p></o:p></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoListParagraphCxSpFirst" style="mso-list: l3 level1 lfo2; text-indent: -.25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> 1.<span style="font: normal normal normal 7pt/normal 'Times New Roman';"> <span class="Apple-style-span" style="color: magenta;"> </span></span><b><span class="Apple-style-span" style="color: magenta;">IL-20</span></b> is a
<b><u style="background-color: magenta;">cytokine</u></b>, a secreted molecule
that regulates inflammation. What
exactly it does is a topic of current research, since it was only discovered 10
years ago. We know that monocytes
are potent secretors of IL-20 and that the cells that express the receptor for IL-20
include: keritonocytes (skin cells) and endothelial cells (line blood
vessels). Much of the work done to
understand IL-20 biological function has been focused on what IL-20 does to
cells expressing the IL-20 receptor.
For this reason, most of what we know about IL-20 is from a variety of
skin and blood vessel-related diseases.
For example, one of the earliest studies revealed that keritonocytes
rapidly divide and produce lots of potent pro-inflammatory cytokines including:
monocyte chemotactic protein-1 (MCP-1) and TNF-alpha.<sup>7</sup> In addition,
generating mice that overexpress IL-20 results in skin abnormalities such as
thickened epidermis and a wrinkled appearance. These novel discoveries initiated scores of experiments
evaluating the role of IL-20 in inflammatory diseases of the skin like
psoriasis and are currently a top therapeutic target to suppress cutaneous
inflammation.<sup> 8</sup> In addition to psoriasis, a similar inflammatory,
disease-promoting role of IL-20 has been established in rheumatoid arthritis<sup>9</sup>,
athersclerosis<sup>10</sup>, and stroke <sup>11</sup>.<sup> </sup></span><br />
<sup><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif; font-size: small;"><br /></span></sup></div>
<div class="MsoListParagraphCxSpFirst" style="mso-list: l3 level1 lfo2; text-indent: -.25in;">
<span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> 2.<span style="font-weight: bold; font: normal normal normal 7pt/normal 'Times New Roman';"> </span><b><u style="background-color: magenta;">Monoclonal
antibodies</u></b><b> </b>are
antibodies that are not only specific for the same antigen, but also recognize
the exact same amino acid sequence on that antigen. Normally when you mount an immune response against something
like a bacterium, for example, your antigen presentation cells (APCs) will ingest the bacteria and chew up into tiny bits. If the APCs stopped there, your B cells wouldn’t get
effectively activated and you wouldn’t be able to make lots of antibodies to
attack the bacteria and protect you from future infections. In order to get these amazing antibody
benefits, the APC must also present those chewed-up bits of bacteria on their
cell surface so that your adaptive immune system (T and B cells) can wake-up
and realize that there is an infection going on. You have millions of T cells in your body, all expressing a
unique T cell receptor to recognize a single stretch of amino acids of an
antigen-those bits put on display by APCs. Once a T cell recognizes its specific antigenic sequence, it
becomes activated and ready to help B cells make loads of antibodies. <b><span class="Apple-style-span" style="color: magenta;">When
a B cell receives T cell help, it rapidly proliferates generating hundreds of B
cells all instructed by the T cells to make an antibody against that specific part
of the bacterium that the T cell just saw.</span> </b> With a little nudge from a T cell, a single B cell divides
into thousands of B cells. When a
B cell divides, it is also going through a dramatic, incredibly unique process
called <b><u style="background-color: magenta;">affinity maturation</u></b>. With each division, a B cell is
rapidly mutating the DNA that codes for the antibody’s specificity. This process results in the production
of thousands of B cells that are all able to recognize that specific bacterium,
but with slightly different affinities.
But remember that T cells are not all the same and have a range of
specificities to any particular antigen, so a variety of different T cells are
doing this to different B cells, which quickly multiplies the number of
different kinds of antibodies generated during an infection. It’s like inviting a couple friends
over for a drink, but then each of your friends decide to invite some of their
friends and their friends invite some of their friends and so on. Before you know it you have a house
full of different people partying it up, having a great time. <b><span class="Apple-style-span" style="color: magenta;">This
is essentially the same thing that happens in your body during an infection, so
the next time you’re sick, remember that you have your partying B cells to
thank for your swollen lymph nodes (and your ability to beat the infection)!</span></b></span></div>
<div class="MsoListParagraphCxSpLast" style="mso-list: l3 level1 lfo2; text-indent: .25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">But what makes our immune system so amazingly
effective is that these B cells must compete for available antigen to promote
their survival and ability to secrete their antibodies they’ve just generated
through affinity maturation.
This selection process weeds out the B cells that made ineffective,
poorly binding antibodies, so that your body is left with the a handful of the
most selective antibodies that bind the tightest to the pathogen. This group of top-tier antibodies is
the end result of a normal immune response and is collectively called, <b><u><span class="Apple-style-span" style="background-color: magenta;">polyclonal antibodies</span>,</u></b> since
there is still some variation among the specificity of antibodies generated,
but they all derived from the same initial B cell.</span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiSI_3zWGGH5ixwcKXmIJQZTH7BvGeyZm7McbTp0zolKXGUtqbF9PfGPohR6gzjoGaC9uW3RsAF2dcOAT_lhYROpuKipd4wBc70IPI5lG7Kv8HV-ZS8LVp3_xExaY1Tb_AKbeMrspvS7XA/s1600/monoclonAB.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="348" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiSI_3zWGGH5ixwcKXmIJQZTH7BvGeyZm7McbTp0zolKXGUtqbF9PfGPohR6gzjoGaC9uW3RsAF2dcOAT_lhYROpuKipd4wBc70IPI5lG7Kv8HV-ZS8LVp3_xExaY1Tb_AKbeMrspvS7XA/s640/monoclonAB.png" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Monoclonal antibody generation in the lab.</span></td></tr>
</tbody></table>
</div>
<div class="MsoListParagraphCxSpFirst" style="text-indent: .25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span class="Apple-style-span" style="color: magenta;"><b>So how do
you get from a variety of antibodies with varying specificity (polyclonal) to a
variety of antibodies with the exact same specificity (monoclonal)? You do it in the lab. </b> </span>Monoclonal antibody production is not something your body
does naturally, because when your body is at war with a pathogen, it’s best to
have as many weapons as possible to use in the attack, right? But, in research, scientists want to
limit variables and find the most specific weapon to develop therapy. In order to do this, all the antibodies
have to be the same. Exact same B
cell. Exact same affinity. Exact same specificity. Exact same antibody made. You get the idea. Ok, so in order to do this, you first
find something you’re interested in making antibodies against, say that
bacterium that infected us in the previous example. In order to make antibodies against the bacterium, you need
an infection, it doesn’t need to be robust or cause disease, but enough to
stimulate B cells, like in a vaccination. <o:p></o:p></span></div>
<div class="MsoListParagraphCxSpMiddle" style="text-indent: .25in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> In the
lab, this is usually done in mice.
After a few weeks since the immunization with the bacterium, the mice
will have hundreds of B cells activated with a polyclonal antibody
repertoire. The spleen is
isolated since that’s where the majority of B cells reside. The antibody-producing B cells are then
isolated and cultured with an immortal cell line to create hybridomas. <b><u style="background-color: magenta;">B
Cell Hybridomas</u></b> are generated so that these B cells can live indefinitely
so that monoclonal antibodies can be obtained, since natural B cells don’t live
for very long in culture. After
selecting for the B cells that have successfully fused with the immortal cell,
then scientists split the hybridomas into a culture plate so that there is only
1 B cell hybridoma per well. Then,
they stimulate each hybridoma with that same antigen you used to immunize the
mice before. Because there are no
variability from T cells and the culture is in single-cell suspension, the single
cell in culture dish will clonally expand, producing identical antibodies. Specific antibodies based on affinity
strength and specificity is further selected for using biochemical techniques,
to result in the acquisition of purified monoclonal antibodies. These monoclonal antibodies then can be
used as reagents for experiments (FACS, Immunoprecipitation,
Immunohistochemistry), blocking antibodies for therapies and experimental
use, or immunotherapies for individuals who cannot mount their own immune
response (i.e. <a href="http://www.rxlist.com/synagis-drug.htm"><span class="Apple-style-span" style="color: magenta;">Synagis</span></a> to
treat infant respiratory syncytial virus)<o:p></o:p></span></div>
<div class="MsoListParagraphCxSpMiddle">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></div>
<div class="MsoListParagraphCxSpMiddle">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><b><i><u>N</u></i></b><b><i><u>ow, with the information above, we can infer: <span class="Apple-style-span" style="color: #363636;"><o:p></o:p></span></u></i></b></span></div>
<div class="MsoListParagraphCxSpMiddle">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span class="Apple-style-span" style="color: #363636;">Antibodies were generated to produce something
that is highly specific for the pro-inflammatory cytokine, IL-20. </span><b><span class="Apple-style-span" style="color: magenta;">This paper is going to provide data revealing that when this anti-IL-20 antibody binds to
IL-20 it blocks monocytes from developing into osteoclasts, thus preventing
osteoporosis.</span></b><span class="Apple-style-span" style="color: #363636;"><o:p></o:p></span></span></div>
<div class="MsoListParagraphCxSpLast">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></div>
<div class="MsoNormal">
<b><i><u><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Ready for an adventure? Read on for a guided-tour
through the scientific data!</span></u></i></b><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgTj-7B-GiUcYEVodF8VCZM7_KIHXRGtItl5Q9mlk2D6RtIcG6Qieg0pKkkZOxxFM6l57ZAhN9g8LeftgUhRgNAxk-x061Hfp1vksb1Aay_vxBjRH39h17J5WFMZ8OXOgNzJe5Cd_GwEgw/s1600/osteoclast.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="250" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgTj-7B-GiUcYEVodF8VCZM7_KIHXRGtItl5Q9mlk2D6RtIcG6Qieg0pKkkZOxxFM6l57ZAhN9g8LeftgUhRgNAxk-x061Hfp1vksb1Aay_vxBjRH39h17J5WFMZ8OXOgNzJe5Cd_GwEgw/s400/osteoclast.png" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Using fluorescent microscopy and nuclear stains, such as DAPI (blue) scientists can visualize multinucleated osteoclasts, how cool is this picture?</span><span class="Apple-style-span" style="font-size: xx-small;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span>From <a href="http://microscope.olympus-global.com/"><span class="Apple-style-span" style="color: magenta;">microscope.olympus-global.com</span></a></span></td></tr>
</tbody></table>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> Although, IL-20 signaling
has been associated with a variety of diseases that share bone-loss as a
symptom, there was yet any data regarding the levels of IL-20 produced in
osteoporotic patients. Therefore,
one of the first things that Hsu and colleagues wanted to assess was whether
IL-20 cytokine levels were elevated in individuals suffering from
bone-loss. To do this, they
compared IL-20 concentration in patient serum between 33 41-60 year-old healthy,
62 41-67 year-old osteopenic and 37 40-81 year-old osteoporotic women. <b><span class="Apple-style-span" style="color: magenta;">Indeed,
circulating IL-20 was significantly increased in women who were clinically
diagnosed with either osteopenia or osteoporosis. </span></b>Of note, this assessment
was limited to Asian women (as the research group is based in Taiwan) and women
with known metabolic bone diseases, diabetes, cancer, renal disease,
athrosclerosis, using steroids or medications known to influence bone-loss were
excluded in this study.</span></div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">
</span><br />
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span><span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> To
examine the role of IL-20 in bone-loss pathology, the researchers utilized a
common mouse model that mimics the disease as seen in humans. The osteoporosis mouse model is
achieved via ovariectomy (OVX).
Similar to what was observed in osteoprotic women, IL-20 found in the
serum of OVX mice was significantly greater compared to normal female mice,
thereby suggesting that the OVX mouse model does, in fact, adequately represent
osteoporosis disease symptoms (rise in IL-20) similar to the women clinically
diagnosed with osteoporosis.</span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">In
a recent study, Hsu and colleagues studied the role of IL-20 in rheumatoid
arthritis (RA). For those
experiments, they generated mouse anti-human IL-20 monoclonal antibodies and
found that these antibodies inhibited IL-20 signaling in RA, which lessened the
severity of the disease. Now, Hsu,
et al. wanted to know if this IL-20-specific antibody would have similar
ability to reduce the severity of disease symptoms in osteoporosis. <span class="Apple-style-span" style="color: magenta;"><u> </u><b><u>They
call this anti-IL-20 monoclonal antibody 7E</u>. In the OVX mouse model, they found that when they treated
these mice for 2 months with 7E, the levels of IL-20 dropped to that of non-OVX
females or <u>OVX mice treated with estradiol, which serve as positive controls
of healthy mice</u></b></span>.
Furthermore, analysis of bone morphology and bone mass density (BMD)
revealed that OVX mice treated with the anti-IL-20 antibody, 7E, exhibited less
bone loss than mice that did not receive 7E. It is important to note, this
research team was quite thorough in their experiments by including a number of
positive and negative controls to justify that the observed effects with 7E was
specific to IL-20. </span></div>
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">To
show that these effects were specific to 7E and not to any injected antibody,
the scientists also included a control group of OVX mice treated with
non-specific antibody (mIgG), which did not attenuate IL-20 levels or
bone-loss. Moreover, by using <a href="http://en.wikipedia.org/wiki/ELISA"><span class="Apple-style-span" style="color: magenta;">ELISA</span></a> in which they coat a
culture plate with the 7E antibody to “capture” serum cytokines followed by a
secondary antibody to detect a variety of cytokines with similar structure to
IL-20, Hsu and colleagues demonstrated that the 7E monoclonal antibody they
generated was specifically recognizing IL-20. <o:p></o:p></span></div>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">
</span><br />
<div class="separator" style="clear: both; text-align: center;">
</div>
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">
</span><br />
<div class="MsoNormal" style="text-indent: .5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">At
this point, there is data to suggest that IL-20 has a role in promoting
bone-loss, since levels of this cytokine increase with disease and neutralizing
the cytokine with an IL-20-specific antibody ameliorates disease symptoms. However, <i>HOW</i> IL-20 is doing this and what cells are responsible for the
IL-20-mediated effects are completely unknown.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Given
what is currently understood about the cells involved in bone resorption, the
research team started to focus on osteoclasts. First, Hsu, et al. tested whether 7E affected the ability to
generate osteoclasts from hematopoietic stem cells (HSCs). As described above, these precursor
cells require M-CSF and RANKL in order to differentiate into osteoclasts. Regardless of when 7E was given to HSCs,
prior to or at the same time as M-CSF/RANKL, <span class="Apple-style-span" style="color: magenta;"><b>7E inhibited osteoclast formation</b></span>
(look for the giant cells!):</span></div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">In
addition to the defect in giant cell formation, treatment with 7E reduced the
expression of a variety of osteoclast markers including: RANK, c-Fos, Cathepsin
K, NFATc1 and TRAP. These data show 7E can be used to block
osteoclast formation in vitro, which for the antibody to have an effect, it
needs to bind IL-20 present in the culture. <b><span class="Apple-style-span" style="color: magenta;">Because there were no other cells present in this culture,
these data indicate that osteoclasts are capable of producing and sensing IL-20
themselves! </span></b><o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">To
determine if these precursor cells were capable of producing IL-20, Hsu and
colleagues looked at IL-20 and IL-20 receptor expression in HSCs. Only in the presence of M-CSF, did HSCs
express IL-20 illustrating that in addition to giant-cell formation, M-CSF
treatment induces IL-20 production in these cells. Furthermore, when these M-CSF-derived osteoclast precursor
cells (monocytes) were treated with exogenous IL-20, RANK expression
significantly increased, suggesting that cells developing into osteoclasts
produce IL-20, and respond to IL-20 by upregulating RANK on their cell
surface. Recall that RANK, is the
receptor for RANKL and is required for osteoclast development and
function. The IL-20 neutralizing
antibody, 7E, was able to greatly diminish RANK expression by osteoclast
precursors, despite the presence of IL-20 in the culture. </span><b><span class="Apple-style-span" style="color: magenta; font-family: Georgia, 'Times New Roman', serif;">These
data provide compelling evidence that IL-20 promotes osteoclast development and that IL-20 may promote osteoporosis.</span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><o:p></o:p></span></b></div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">These
cells may enhance RANK expression on their cell surface to enhance their
ability to sense and bind available RANK ligand (RANKL) in the bone
environment. The idea is that the
more RANK or RANKL available, the more monocytes are developing into
osteoclasts that lead to degradation of bone. To further assess how IL-20
affects in bone development, the research team looked into how IL-20 affects
osteoblast function. In an
osteoblastic cell line culture, IL-20 enhanced osteoblast signaling activity
and RANKL expression. Currently, the understanding of the induction pathway of
osteoclast development begins with RANKL stimulating RANK on M-CSF-stimulating
osteoclast precursor cells. <b> <span class="Apple-style-span" style="color: magenta;">But here, Hsu, et al. provide data
showing that something upstream of RANK/RANKL is controlling RANK/RANKL
function and therefore ultimately controlling osteoclast development--IL-20!</span></b> These are the first data indicating how
RANK and RANKL expression is modulated by a soluble factor associated with bone
disease! <o:p></o:p></span></div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">To
further investigate the role of IL-20 signaling in promoting osteoporosis, the
research team generated IL-20R1 knockout mice. By removing the ability of IL-20 to stimulate signaling
cascades responsible for osteoclast development, they observed that aging mice
lacking IL-20R1 had increased BMD compared to wild-type counterparts. In addition, mice lacking IL-20R1 had a
defect in osteoclast development from monocytes and were unresponsive to IL-20
or 7E treatment, thus further accentuating the specificity of 7E for
IL-20. So perhaps, humans, like
mice may lose the ability to maintain high levels of IL-20R1 thereby increasing
the chance of developing more bone resorbing osteoclasts. However, Hsu and colleagues did not
investigate whether similar data regarding IL-20 receptor expression is
observed in humans.<span class="Apple-style-span"><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Lastly,
Hsu, et al. went back to see if the IL-20R deficiency provided similar results
as their IL-20 blocking antibody, 7E in the development of osteoporosis. To do this, they performed
ovariectomies (OVX) on IL-20R1 deficient (IL-20R1-/-) and IL-20R1 sufficient
(IL-20R1+/+;+/-) mice. <b><span class="Apple-style-span" style="color: magenta;">Similar to what they observed in mice
treated with 7E, OVX mice lacking IL-20R were protected from bone-loss!</span></b></span> <span class="Apple-style-span" style="font-family: Arial, Helvetica, sans-serif;"><o:p></o:p></span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgAlUwSqKaX9CVDX7wNoP5-8WGItSesmcW9KXBMhXrT5hi6lJ3MQIzigDUcB87lRHkyRRpPLrg289HhIR_ajYuAyLZ4b6yDW0KVqCTKHIfbeJviwhL-2zQ6ROMrVRY9-dT6RRZdwBrEZyc/s1600/1208Jossefig1.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="416" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgAlUwSqKaX9CVDX7wNoP5-8WGItSesmcW9KXBMhXrT5hi6lJ3MQIzigDUcB87lRHkyRRpPLrg289HhIR_ajYuAyLZ4b6yDW0KVqCTKHIfbeJviwhL-2zQ6ROMrVRY9-dT6RRZdwBrEZyc/s640/1208Jossefig1.jpg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">This diagram depicts what was known about osteoclast function, what Hsu, et al. were able to add was data to answer the question: WHAT regulated RANK/RANKL expression? <b>Hsu, et al. showed for the first time that IL-20 upregulated RANK/RANKL and that an IL-20-specific antibody could block this expression and IMPROVE osteoporosis symptoms!</b> Importantly, they also demonstrated that IL-20 may be used as a potent diagnostic marker to indicate the presence of osteoporosis in humans!! </span><span class="Apple-style-span" style="font-size: xx-small;">Figure from <a href="http://healthplexus.net/"><span class="Apple-style-span" style="color: magenta;">HealthPlexus.net</span></a></span></td></tr>
</tbody></table>
</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">By
utilizing a variety of methods including generating IL-20-specific blocking
monoclonal antibodies and generating IL-20R-deficient mice, Hsu and colleagues
convincingly provide data that are <span class="Apple-style-span" style="color: magenta;"><b><u>the
first</u> to describe the role and function of IL-20 in promoting
osteoporosis. Importantly, <u>this is
also the first report</u> describing the positive correlation between IL-20 serum
levels and bone-loss disease. </b> </span>These findings lend insight and development of better
diagnostic tools that may detect the onset of bone-loss earlier than current
diagnostic methods. More research
is needed to elucidate the kinetics of IL-20 production in order for IL-20 to
be effectively used as a <span class="Apple-style-span" style="color: magenta;"><a href="http://en.wikipedia.org/wiki/Biomarker"><span class="Apple-style-span" style="color: magenta;">biomarker</span></a>
</span>to track the onset and progression of bone disease.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-indent: 0.5in;">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">The
current clinical treatments for bone-loss include drugs that largely target
estrogen, calcium, or RANK/RANKL signaling. The disadvantages to the former two are highlighted in the
above section; however it is important to note that in mice, genetic deletion
of either RANK or RANKL results in severe osteopetrosis (increased bone mass)
and the utter loss of osteoclasts.
Which although may cure osteoporosis, it leads to poor bone homeostasis
and may cause detriment to immune cell and bone development. Because of these findings, there is
potentially a danger in developing osteopetrosis with individuals with
RANK/RANKL mutations or using drugs that completely block RANK/RANKL function.<sup>12</sup>
Because of this, <b><span class="Apple-style-span" style="color: magenta;">it is imperative for
researchers to continuously unveil new understandings in signaling pathways and
be scavenging for new therapeutic targets in order to achieve the most
effective drugs with the least amount of harmful side effects.</span></b> Studies, such as this one lead by
Ming-Shi Chang at the National Cheng Kung University in Taiwain, is a testament
to the encouraging role academic scientists play in developing promising, novel
immunotherapies to help treat millions of people around the world.</span></div>
</div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_white.png" style="border: 0;" /></a></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+experimental+medicine&rft_id=info%3Apmid%2F21844205&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Anti-IL-20+monoclonal+antibody+inhibits+the+differentiation+of+osteoclasts+and+protects+against+osteoporotic+bone+loss.&rft.issn=0022-1007&rft.date=2011&rft.volume=208&rft.issue=9&rft.spage=1849&rft.epage=61&rft.artnum=&rft.au=Hsu+YH&rft.au=Chen+WY&rft.au=Chan+CH&rft.au=Wu+CH&rft.au=Sun+ZJ&rft.au=Chang+MS&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Aging%2C+Cancer%2C+Cardiovascular%2C+Clinical+Research%2C+Pharmacology%2C+Physiology%2C+Genetics%2C+Pathology%2C+Metabolism%2C+Hematology">Hsu YH, Chen WY, Chan CH, Wu CH, Sun ZJ, & Chang MS (2011). Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. <span style="font-style: italic;">The Journal of experimental medicine, 208</span> (9), 1849-61 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21844205" rev="review"><span class="Apple-style-span" style="color: magenta;">21844205</span></a></span><span class="Apple-style-span" style="color: magenta;"> </span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"><b><i><br /></i></b></span><br />
<b><i><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"><br /></span></i></b><br />
<b><i><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">References and Further Reading:</span></i></b></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">1. Glick,B. “<a href="http://www.sciencedirect.com/science/article/pii/016524279190003U"><span class="Apple-style-span" style="color: magenta;">Historical
perspective: The bursa of Fabricius and its influence on B cell development,
past and present</span></a>”. <i>Veterinary
Immunology and Immunopathology</i>. 30:3-12. (1991).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">2. Yasuda, H. “<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC19881/"><span class="Apple-style-span" style="color: magenta;">Osteoclast
differentiation factor is a ligand for
osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to
TRANCE/RANKL</span></a>”. <i>PNAS</i>.
95:3597-3602. (1998).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">3. Arron, J. and Choi, Y. “<a href="http://www.nature.com/nature/journal/v408/n6812/full/408535a0.html"><span class="Apple-style-span" style="color: magenta;">Bone
versus immune system</span></a>”. <i>Nature</i>.
408:535-536. (2000).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">4. Yasothan, U. and Kar, S.
“<a href="http://www.nature.com/nrd/journal/v7/n9/full/nrd2620.html"><span class="Apple-style-span" style="color: magenta;">Osteoporosis:
overview and pipeline</span></a>”. <i>Nature
Reviews Drug Discovery. </i>7:725-726. (2008).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">5. Hughes, DE. “<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC303914/"><span class="Apple-style-span" style="color: magenta;">Inhibition of
osteoclast-like cell formation by bisphosphonates in long-term cultures of
human bone marrow</span></a>”. <i>J. Clin. Invest</i>.
83:1930-1935. (1989).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">6. Opar, A. “<a href="http://www.nature.com/nrd/journal/v8/n10/full/nrd3015.html"><span class="Apple-style-span" style="color: magenta;">Late-stage
osteoporosis drugs illustrate challenges in the field</span></a>”. <i>Nature Reviews Drug Discovery</i>. 8:
757-758. (2009).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">7. Sabat, R. “<span class="Apple-style-span" style="color: magenta;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/17465720"><span class="Apple-style-span" style="color: magenta;">IL-19 and IL-20: two novel
cytokines with importance in inflammatory diseases</span></a>”. </span><i><span style="text-decoration: none;">Expert Opin Ther Targets.</span>
</i>11:601-612. (2007).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">8. Rich, BE. “<a href="file://localhost/IL-20/%20a%20new%20target%20for%20the%20treatment%20of%20inflammatory%20skin%20disease"><span class="Apple-style-span" style="color: magenta;">IL-20:
a new target for the treatment of inflammatory skin disease</span></a>”. <i><span style="color: black; text-decoration: none;">Expert Opin Ther Targets.</span> </i><span style="color: black;"> 7:165-74. (2003).<o:p></o:p></span></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">9.Hsu, YH., et al. “<a href="http://www.ncbi.nlm.nih.gov/pubmed/16947773"><span class="Apple-style-span" style="color: magenta;">Function of interleukin-20
as a proinflammatory molecule in rheumatoid and experimental arthritis</span></a>”. <i>Arthritis Rheum.</i> 54:2722-2733. (2006).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">10. Chen, WY. “<a href="http://atvb.ahajournals.org/content/26/9/2090.full.pdf"><span class="Apple-style-span" style="color: magenta;">IL-20 is
expressed in atherosclerosis plaques and promotes atherosclerosis in
apolipoprotein E-deficient mice</span></a>”. <i style="color: black;">Arterioscler
Thromb Vasc Biol</i> .26:2090-2095. (2006).<o:p></o:p></span></div>
<div class="MsoNormal">
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="color: black;"><span class="Apple-style-span" style="font-size: x-small;">11. </span></span><span class="Apple-style-span" style="font-size: x-small;">Chen, WY and Change, MS. “<a href="http://www.jimmunol.org/content/182/8/5003.short"><span class="Apple-style-span" style="color: magenta;">IL-20 is regulated by
hypoxia-inducible factor and up-regulated after experimental ischemic stroke</span></a>”.
<i>Journal of Immunology</i>. 182:5003-5012.
(2009).</span></span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">12: Kong, YY, et al. “<a href="http://www.nature.com/nature/journal/v397/n6717/abs/397315a0.html"><span class="Apple-style-span" style="color: magenta;">OPGL
is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node
organogenesis</span></a>”. <i>Nature</i>.
397:315-333. (1999).</span><br />
<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span class="Apple-style-span" style="font-size: x-small;">
</span></span></div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com22tag:blogger.com,1999:blog-5699986821429190705.post-56020788118042303092011-08-19T11:02:00.000-07:002011-11-13T19:27:40.543-08:00Thinking Small To Save Big: new research combines nanotechnology with immunology to develop an inexpensive, accurate diagnostic tool for the developing world<style>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi4uRCAuLahFF6Qy6kPY9m66evFHCjzMd9KT7IPguoIc2bb925kmP4J5GJ3X46UwS1n1ctGmiWpHwovmlIDposGsjbOaJp5J9EW3sXbyf424NOGyw-gRvab2gLu0ui-yvhcT46sD4Sx8rs/s1600/HIV-budding-Color.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="212" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi4uRCAuLahFF6Qy6kPY9m66evFHCjzMd9KT7IPguoIc2bb925kmP4J5GJ3X46UwS1n1ctGmiWpHwovmlIDposGsjbOaJp5J9EW3sXbyf424NOGyw-gRvab2gLu0ui-yvhcT46sD4Sx8rs/s320/HIV-budding-Color.jpg" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">SEM image of HIV virons (green) infecting a CD4+ T cell (red)</span><span class="Apple-style-span" style="font-size: xx-small;"> from </span><a href="http://cdc.gov./" style="font-size: x-small;"><span class="Apple-style-span" style="color: magenta;">CDC.gov.</span></a></td></tr>
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<span style="font-size: small;"><b><i><u>Public Interest Note:</u></i></b></span></div>
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<span style="font-size: small;"> Can you live on an annual salary of less than $2,000? Even if you could somehow, manage to have some clothes, water, food and shelter, what happens when you get sick? These are the difficulties facing the millions of people living in resource-poor countries. Resource-poor countries are often plagued by a combination of factors including: dense population, low GDP per capita, economic and political instability.</span> <style>
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</style> <span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><sup>1</sup></span> <span style="font-size: small;"> Consequently, these countries often have weak health care systems and lack the finances and proper education in combating these countries’ biggest health challenges. Additionally, these countries are typically the most disease-ridden areas in the world. The most prevalent diseases that affect areas of the world such as Sub-Saharan Africa, Indonesia, and India are not the ones we, in America, see as threat, because </span><span style="font-size: small;">despite our current economic woes we can afford valuable education and treatments for these diseases. </span><span style="font-size: small;">Thanks in part to huge scientific and medical advances in vaccination, education, and preventative strategies, the developed world has been able to lower the rate of new cases of HIV/AIDS, tuberculosis, and malaria.</span> <span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"> <sup>2</sup></span><style>
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<tr style="font-family: Georgia,"Times New Roman",serif;"><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-size: x-small;"> </span><span class="Apple-style-span" style="font-size: xx-small;">From Tortora, B. "</span><a href="http://www.gallup.com/poll/145787/sub-saharan-africans-struggle-financially-even-gdp-grows.aspx" style="color: magenta; font-size: x-small;">Sub-Saharan Africans Struggle Financially Even as GDP Grows</a><span class="Apple-style-span" style="font-size: xx-small;">". </span><i style="font-size: x-small;">Gallup</i><span class="Apple-style-span" style="font-size: xx-small;">. (Jan. 2011)</span></td></tr>
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<span style="font-size: small;">Unfortunately, technology is generally expensive. Expensive to produce and subsequently expensive to distribute and purchase. Common diagnostic tests performed in U.S. hospitals can cost upwards of a few hundred dollars each. And that’s the cost for the patient, these prices do not incorporate what it costs the hospital to purchase the test from the drug manufacturing company, the cost in paying trained individuals to administer and interpret the test, or any external equipment needed such as electronics and labware! Although, there have been recent successes in lowering the cost of antiviral drugs in developing countries, there remains a lack of affordable, by means of the developing world, to receive the same quality of accurate and effective diagnostic testing we receive in America. </span></div>
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<span style="font-size: small;"><b style="color: magenta;">The exciting thing is, is that despite this particularly difficult endeavor, the scientific community continues to strive to discover innovative ways to improve health in these areas. </b>The newest published research from <a href="http://www.bme.columbia.edu/~sia/" style="color: magenta;">Samuel Sia’s laboratory at Columbia University</a> exemplifies the ultimate goals, I hope every scientist seeks: to utilize both creativity and intellect to discover something meaningful that will better the world. </span></div>
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<span style="font-size: small;">Sia and colleagues present a novel diagnostic device the size of an index card that has the ability to screen for multiple diseases simultaneously! <b><span style="color: magenta;">Besides the awesome science behind it (discussed below), the test, itself occurs on a small chip costing as little as $1 to produce, which then is quickly analyzed by a machine “as inexpensive and simple to use as a cellular phone”, and requires little to no training to interpret the results.</span></b> Oh, did I mention the whole test requires a single drop of blood and only takes 15-20 minutes to complete? A patient can receive results from a single pinprick to results in hand in less than a half an hour!</span> <style>
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</style><span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><sup>3</sup></span> </div>
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<span style="font-size: small;">There is no doubt that this technology will be beneficial to resource-poor countries and will help instigate a movement to develop more diagnostic tests in the future, the only problem is: who will fund this kind of production? Such developments need the public’s constant support by understanding the science, providing funding and enhancing communication between scientists and companies that manufacture and distribute these novel devices. Increased support within the public will likely result in providing these diagnostic tools to resource-poor countries while while keeping the cost as minimal as possible. </span></div>
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<span style="font-size: small;"> </span><span style="font-family: Arial;"></span> <style>
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<span style="font-size: small;"><b><i><u>Developing New Diagnostic Tools: Why This Research Matters</u></i></b></span></div>
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<span style="font-size: small;"> Sia and his research team set out to design a new diagnostic tool that would be able to accurately screen people for two of the most common infectious diseases in developing countries: HIV and syphilis. The authors of the published paper explain they “chose an HIV-syphilis combination test because HIV and syphilis are treatable in diagnosed pregnant mothers, for whom short-course antiretroviral prophylaxis reduces transmission of HIV, and treatment with penicillin reduces congenital syphilis, which can be fatal for the newborn”. </span> <style>
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</style><span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><sup>3</sup></span> <span style="font-size: small;"> By focusing on diseases that are passively transmitted from mother to baby, the scientists hope to increase the rate of treating infected individuals and subsequently improving the overall healthcare in infectious disease ridden countries. Sounds like a pretty amicable quest right? <b style="color: magenta;">Not only would there be hurdles designing the world’s first-ever multi-diagnostic test for these diseases, but the goal was to achieve all of this with quickest results return rate as possible.</b><b style="color: magenta;"> </b> </span></div>
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<span style="font-size: small;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> How do scientists think of ways to do this? They think small: small devices, small patient samples, small amount of reagents needed, etc. All of this adds up, theoretically, to a small cost to the patient. The most common testing technology that fits these criteria is categorized as </span><a href="http://www.pointofcare.net/" style="color: magenta; font-family: Georgia, 'Times New Roman', serif;">point-of-care testing (POCT). </a><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> The purpose of POCT is to provide on-site immediate medical diagnoses that are portable for patients-no matter if they live in a big city, in the country, or in the most isolated, resource-poor habitats in the world. Commonly used POCTs include: individual blood-glucose tests, pregnancy test strips, and rapid agglutination tests for blood-typing. All of these examples are extremely valuable tools because not only are the tests reliable, but they are also inexpensive, easy to use, easy to interpret, and require the minimal amount of external equipment, thus keeping the cost low. All of the mentioned POCTs test for harmless molecules, but how do you keep the convenience of POCTs in mind when designing a tool that is going to detect highly infectious agents? </span></span></div>
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<span style="font-family: Arial;"> <span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"> </span><span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">For a long time, it was believed that microscopy was the only way to detect pathogens in an infected person’s blood. Because you can literally see the presence of a particular bacteria, virus, or parasite, thanks to a variety of dyes and light maneuvering microscopy techniques, you can confidently determine if someone was in fact infected with a deadly microbe. However, microscopes are expensive (as a point of reference, the cheaper student-microscopes used in the General Microbiology Labs I teach, are worth hundreds of dollars each and don’t offer any fancy optics!). Notably, microscopy done right is not as easy as one might believe, it requires extensive training which requires more money in addition to thousands of dollars spent for the microscope, lens, slides, dyes and reagents needed. Furthermore, microscopes are generally not the most accessible devices, it seems quite challenging to lug a microscope into the middle of the Congo, for example, without somehow breaking one of the objective lens. According to a recent review article on the impact of POCTs on global health, “over a century of poor microscopy performance has contributed to the culture of mistrusts and undervalue of diagnostic test results by health care providers in low-resource settings”. </span></span> <style>
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</style><span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><sup>4</sup></span> </div>
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<span style="font-size: small;"> For these reasons, health care providers in developing countries have turned to <u><b><span style="background-color: magenta;">immunoassays</span></b></u>, which rather than seeing whole microbes, can quantify how much of pathogenic protein is present in a patient’s blood sample.</span></div>
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<span style="font-size: small;"><b><i><u>Screening for Infections in Developing Countries: Challenges and Advances</u></i></b></span></div>
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<span style="font-size: small;"> POCTs represent a fantastic example of cooperation between scientists, engineers, businesses and public health personnel. There are the biological research laboratories that focus on identifying <b style="background-color: magenta;"><u>antigens</u></b>, molecules that stimulate the immune response, associated with certain infectious diseases, the engineers who then figure out a way to detect these antigens in biological samples, and finally there is the mass-production and distribution of these diagnostic devices by businesses and global health agencies. </span></div>
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<span style="font-size: small;"> One of the biggest challenges in designing the most effective POCTs, that is the ones that can realistically be used in the field no matter the location or finances available, are ones that can operate with as little equipment as possible. This is particularly important for resource-poor countries such as ones located in Sub-Saharan Africa. Biosaftey and waste disposal tend to be quite poor in developing country clinical facilities, which is especially a concern for areas plagued by high infectious disease rates. Improper handling of needles, culture plates, tubes, pipet tips, and any other equipment that stores biological samples, increases the spread of disease and further hinder a country’s overall health care.</span> <span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><sup>4</sup> </span><style>
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</style><span style="font-size: small;"> For this reason, the most commonly used POCT to detect pathogenic infection currently is the <a href="http://www.rapid-diagnostics.org/tech-lateral.htm" style="color: magenta;">lateral flow test</a><span style="color: magenta;">. </span></span></div>
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<span style="font-size: small;">Lateral flow tests are also called immunochromatic strip (ICS) tests: “immuno” meaning antibodies are used to detect an antigen present in a sample and “chromatic” indicating that some sort of chromatography will be used to visualize the result of the test. Lateral flow tests are very simple and consist of a small strip of nitrocellulose that has some antibody bound to it at one end of the strip. On the opposite end of the antibody spot, a small blood sample, obtained from a pinprick, is mixed with a buffer that will help carry the blood through the entire nitrocellulose strip simply by capillary action. If a person has the antigen present in their blood that the bound antibody recognizes, it will stick to the strip. As more antigen accumulates on the antibody strip, the strip will produce a visible line to indicate the presence of that antigen. This is the most common method to currently detect malaria and HIV in developing countries. As perhaps, a more easily understood example of lateral flow tests in action, this is the mechanism behind how take-home pregnancy tests work too! So why invent something new? How could these screening for infectious diseases be improved upon for resource-poor nations?</span><br />
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<span style="font-size: small;"><b><i><u>The “mChip”: The Immunology Behind the Technology</u></i></b></span><br />
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<span style="font-size: small;">Those were the questions that motivated Sia and his research team to create the “<b>m</b>obile <b>M</b>icrofluidic <b>c</b>hip for <b>i</b>mmunoassay on <b>p</b>rotein markers” or the "mChip" for short (a bit more catchy too right?!). <b><span class="Apple-style-span" style="color: magenta;">Essentially, the</span></b> <b style="color: magenta;">mChip is a full laboratory-based assay shrunk down to fit on a plastic chip not much bigger than a credit card. </b><b style="color: magenta;">The strongest advantage the mChip has over lateral flow tests is that you can screen for multiple antigens or diseases at the same time!</b></span></div>
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<span style="font-family: Arial;"> <span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">So how does the test work? Well, part of the name is immunoassay, so again, this test utilizes antibodies specific for certain antigens associated with disease. The laboratory-based test that is miniaturized is the<b> <a href="http://en.wikipedia.org/wiki/ELISA" style="background-color: magenta; color: black;">Enzyme-linked Immunosorbant Assay (ELISA).</a><span style="background-color: magenta;"> </span> </b>The ELISA, is perhaps the most commonly used immunological test in the world and is used everywhere from hospitals to academic research labs to undergraduate immunology courses. ELISAs are an extremely valuable test because: 1) you can test multiple samples simultaneously, 2) is very good for detecting even small amounts of antigen and 3) the results are typically colormetric, making the interpretation of results simpler. You can detect very small amounts of antigen that usually is below the threshold of detection in other screening strategies, because of the Enzyme-linked detection antibodies used in the assay. </span></span><br />
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<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">Diagram illustrating an ELISA done commonly in labs in hospitals to test for the presence of disease-related antibodies and pathogens. <b>The mChip miniturized this whole assay onto a polystyrene chip and used metal nanoparticles in place of enyzmes to simplify the technique.</b></span><span class="Apple-style-span" style="font-size: xx-small;"> From <a href="http://signosisinc.com/"><span class="Apple-style-span" style="color: magenta;">signosisinc.com</span></a></span></td></tr>
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<span style="font-size: small;"> An ELISA begins by coating a 96-well polystyrene plastic plate with a capture antibody (that’s right you can test 96 samples at once!). The capture antibody is an antibody that is specific for a particular antigen, say <b style="color: magenta;"><u>gp41- a well-known HIV antigen</u></b>. Polystyrene plastic is used because it binds proteins extremely tightly, which is important when you need to wash the plate to remove unbound antigen. By removing anything that doesn’t stick to the capture antibody, the level of background interference decreases dramatically. So if a person has HIV, the gp41 will stick to the capture antibody on the plate, but how will you visualize this? That’s where the enzyme-linked antibody comes into play. In an ELISA, a second antibody is used to detect the bound antigen. Think of this as a sandwich: where on a plate there’s an antigen trapped between two antibodies-both antibodies detect the same antigen. This second, detection antibody is covalently linked to an enzyme, so you can add a particular substrate that if the enzyme-linked antibody is stuck to the plate, will cleave the substrate revealing a color. Therefore in a typical ELISA, the darker the color means the more enzyme there is, thus the more antigen there is detected in the sample!</span></div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: Arial;"> </span></b><span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><b style="color: magenta;">By greatly reducing the volumes of reagents used, and shrinking the plate to a polystyrene chip with seven channels, Sia and his team effectively minimized the size of a typical laboratory-based ELISA.</b> This sounds great, but based on personal experience, ELISAs take a long time to complete. Each step has to be incubated for about an hour and involves a lot of pipetting and waste, so this wouldn’t really work for a resource-poor environment. <b><span class="Apple-style-span" style="color: magenta;">To circumvent these concerns, the mChip utilizes microfluidics and multistep reactions to significantly reduce the amount of time and labware needed to do the test! The chips come pre-coated with specific capture antibodies so the only part that would have to be done in the field is running the sample.</span></b> All the pipetting and experimental techniques are replaced with a small tube that a field technician can easily prepare by simple syringe-induced vacuum so no reagents will contact the syringe itself.</span><br />
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"> Another innovative difference between the classic ELISA and the mChip is that instead of using enzyme-linked detection antibodies, the mChip uses gold nanoparticles attached to secondary antibodies. After the secondary, gold-linked antibodies are loaded into the chip, a flush of silver nanoparticles flow through the chip. The silver nanoparticles will react with any bound gold nanoparticles, resulting in the release of light-emitting silver ions. </span><br />
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"> These ions can then be exposed to an inexpensive, simple optical beam such as light-emitting diodes (LEDs) and generate a visible signal within-get this- 10-15 minutes!! Because the compact LED device has an imaging screen, a technician can quickly and easily see the results. </span><br />
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<span style="font-size: small;">What else makes the mChip advantageous over lateral flow tests? Another caveat to currently available screen tests, is the subjectivity of interpreting results. This is especially true for developing countries where efficient training is lacking. For example, it can be difficult for one to distinguish between a negative result and a positive result if the dye on the strip is not super strong. When there is no clear threshold or value placed on an observation, it is up to the experience of the available technician to conclude the results of the test. To correct for this, the Columbia University bioengineering team developed a simple compact device costing less than $1 per unit hat converts the light emitted to an electronic signal. No calculations are required of the clinic-so by simply seeing a signal greater than that of background (a sample run without any blood), indicates a positive result. </span></div>
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<span style="font-size: small;">Pretty cool, right? But, does this new technology work in reality, in the field-say, for example in Rwanda? That’s exactly where the team started to test their mChip, where nearly 3% of the nation is infected with HIV and turnaround times for on-site ELISA tests can take several weeks to obtain. By using only a pinprick of unprocessed whole blood, the mChip was used to screen the presence of HIV (gp41) and syphilis (TpN17). According tothe study, <span style="color: magenta;">“</span><b style="color: magenta;">the assay took less than 15 minutes to complete. Out of a total of 70 specimens with known HIV status, only one tested false, resulting in overall sensitivity of 100% (98.9-100) and specificity of 96% (88.7-100), rivaling the accuracy of lab-based HIV testing”</b>. Similar results were obtained for syphilis detection with 94% sensitivity and 76% specificity with samples collected in Project Ubuzima in Rwanda. </span> <style>
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</style><sup><span style="font-family: Arial;">3 </span></sup><span style="font-size: small;">Importantly, the lab also tested the stability of reagents used for the mChip, and noted that they remain stable for at least 6 months at room temperature. This is especially important for it to be used in areas where refrigeration is hard to find.</span></div>
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<span style="font-size: small;"><b><i><u>What’s Next: From Experimental Research to Distribution</u></i></b></span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-size: x-small;">A prototype to model the mChip and detector that would like to be distributed and used in the future.</span><span style="font-size: xx-small;"> </span><br />
<span style="font-size: xx-small;">From <a href="http://popsci.com/" style="color: magenta;">popsci.com</a></span></td><td class="tr-caption" style="text-align: center;"><br /></td><td class="tr-caption" style="text-align: center;"><br /></td></tr>
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<span style="font-size: small;"> By incorporating physics and microfluidics, the mChip has the potential to deliver advanced immunological diagnostic tests to resource-poor countries. Currently, the mChip is still in the early design phases, due to limited resources for such academic-based studies. It will take more funding and people to actually design the mChip that Sia envisions that will actually be distributed throughout the world. It will take more funding and public support to cover production and distribution of the mChip. This research was supported largely by the National Institutions of Health and is a contender for a $14 million dollar grant sponsored by USAID, the Gates Foundation and other agencies as part of the <b style="color: magenta;"><span style="color: magenta;">“</span><a href="http://www.savinglivesatbirth.net/" style="color: magenta;">Saving Lives at Birth</a>” challenge</b>. Sia’s research team explains in the paper, that the “ultimate goal of this research is to develop a device for infectious-disease screening of pregnant women located in remote areas to prompt early treatment”. <b style="color: magenta;">This technology has great potential in reducing infectious-disease prevalence in the world, but needs further support to develop this potential into reality.</b></span><br />
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<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_white.png" style="border: 0;" /></a></span>
<span class="Z3988" style="font-size: x-small;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+medicine&rft_id=info%3Apmid%2F21804541&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Microfluidics-based+diagnostics+of+infectious+diseases+in+the+developing+world.&rft.issn=1078-8956&rft.date=2011&rft.volume=17&rft.issue=8&rft.spage=1015&rft.epage=9&rft.artnum=&rft.au=Chin+CD&rft.au=Laksanasopin+T&rft.au=Cheung+YK&rft.au=Steinmiller+D&rft.au=Linder+V&rft.au=Parsa+H&rft.au=Wang+J&rft.au=Moore+H&rft.au=Rouse+R&rft.au=Umviligihozo+G&rft.au=Karita+E&rft.au=Mwambarangwe+L&rft.au=Braunstein+SL&rft.au=van+de+Wijgert+J&rft.au=Sahabo+R&rft.au=Justman+JE&rft.au=El-Sadr+W&rft.au=Sia+SK&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Clinical+Research%2C+Pathology%2C+Infectious+Disease%2C+Technology">Chin CD, Laksanasopin T, Cheung YK, Steinmiller D, Linder V, Parsa H, Wang J, Moore H, Rouse R, Umviligihozo G, Karita E, Mwambarangwe L, Braunstein SL, van de Wijgert J, Sahabo R, Justman JE, El-Sadr W, & Sia SK (2011). Microfluidics-based diagnostics of infectious diseases in the developing world. <span style="font-style: italic;">Nature medicine, 17</span> (8), 1015-9 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21804541" rev="review"><span class="Apple-style-span" style="color: magenta;">21804541</span></a></span><br />
<span style="font-size: x-small;"><b style="color: magenta;"><u><i><span style="color: black;"><span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"><br /></span></span></span></i></u></b></span><br />
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<span class="Apple-style-span" style="font-size: x-small;"><b style="color: magenta;"><u><i><span style="color: black;"><span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;">References and Further Reading:</span></span></span></i></u></b><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;"> </span></span></span></span><br />
<span style="font-size: x-small;"><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;">1: Quet, F., et al. "</span></span></span></span><span style="font-size: x-small;"><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518566/" style="color: magenta;">Challenges of epidemiological research on epilepsy in resource-poor countries</a>".<i> Neuroepidemiology</i>. 30: 3-5. (2008)<span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;"> </span></span></span></span><br />
<span style="font-size: x-small;"><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;">2: IB Times Staff Reporter. "<a href="http://www.ibtimes.com/articles/190205/20110801/study-low-cost-disposable-blood-cards-to-offer-easy-hiv-and-syphilis-checks-in-developing-countries.htm" style="color: magenta;">Lab on Chip to Offer, Cheaper, Faster HIV Test</a>". (Aug. 2011)</span></span></span></span><br />
<span style="font-size: x-small;"><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;">3:</span></span></span></span><span style="font-size: x-small;">Chin, C., et al. "<a href="http://www.nature.com/nm/journal/v17/n8/abs/nm.2408.html#/supplementary-information" style="color: magenta;">Microfluidics-based diagnostics of infectious diseases in the developing world</a>". <i>Nature Medicine</i>. 17:1015-1019. (2011).<span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;"> </span></span></span></span><br />
<span style="font-size: x-small;"><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;">4: </span></span></span><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;">Yager, P., et al. "<a href="http://www.ncbi.nlm.nih.gov/pubmed/18358075" style="color: magenta;">Point-of-care Diagnostics for Global Health</a>". <i>Annu. Rev. Biomed</i>. </span></span></span></span><span style="font-size: x-small;"><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;">10:107–44 </span></span></span></span><span style="font-size: small;"><span style="font-size: x-small;"><span style="color: magenta;"><span style="color: black;"><span style="font-family: Georgia, 'Times New Roman', serif;">(2008).</span></span></span></span></span></div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com258tag:blogger.com,1999:blog-5699986821429190705.post-66299348970710946282011-08-13T23:38:00.000-07:002011-11-03T11:54:13.145-07:00T cells Receive Molecular Ammo to Kill Cancer: new research highlights the great potential of immunotherapy to treat leukemia<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2_CImaOcsO_LvEmvN0jltvqgTwOoF_dzoy1izANrOVb5PD97xgCbMliWRIN1VvcWKT3Dcq4PScNoT94V9im5hg9IsNgE_oj0OPtngxy1alKUH2OEslBbcvt0iljkdIaHhzT4oX47txsQ/s1600/cytotoxic-t-cells.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="292" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2_CImaOcsO_LvEmvN0jltvqgTwOoF_dzoy1izANrOVb5PD97xgCbMliWRIN1VvcWKT3Dcq4PScNoT94V9im5hg9IsNgE_oj0OPtngxy1alKUH2OEslBbcvt0iljkdIaHhzT4oX47txsQ/s400/cytotoxic-t-cells.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">T cells (Blue) attacking a cancer cell (white) in vitro. From <a href="http://home.ccr.cancer.gov/inthejournals/itj-therapy.asp" style="color: magenta;">The Center for Cancer Research</a></span></td></tr>
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<span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;"><u><b><i>Spotted: Good Scientific Journalism!</i></b></u></span></span><br />
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<span style="font-size: small;">The popular media has all been a buzz this week over an exciting new study about a new possible cancer treatment. As a PhD Immunology Student, I have to begin by complementing NPR science reporter, <a href="http://www.npr.org/people/2101004/joe-palca" style="color: magenta;">Joe Palca</a> for his post on the NPR Health Blog, <i><a href="http://www.npr.org/blogs/health/2011/08/11/139536661/gene-therapy-breakthrough-trains-immune-system-to-fight-leukemia?ft=1#commentBlock" style="color: magenta;">Shots</a> </i>for 1) describing the basics behind immunotherapy in a way for the public to understand and 2) for "warning" the reader that the sample size is very small and that this is preliminary research. Both points are important to state clearly, as often we, the public, reads a brief story about a new therapy and we instantly want to use it and have it work 100%. Although, the sample size of this study was merely 3 individuals, the fundamental technique and findings offer great promise in the development of the most effective, least invasive treatments to combat cancer.</span></div>
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<u><i><b><span style="font-size: small;">Gene Therapy: Engineering Cells to Cure Disease</span></b></i></u></div>
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<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-size: x-small;">Basic procedure behind gene therapy whereby a patient's own T cells are isolated then engineered to express a certain protein it didn't express before, then the engineered T cells are injected back into the patient to help fight the disease. </span><span style="font-size: xx-small;">From <a href="http://attack-cancer.org/"><span class="Apple-style-span" style="color: magenta;">attack-cancer.org</span></a></span></td></tr>
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<span style="font-size: small;">A University of Pennsylvania research team, lead by renowned tumor immunologist, <a href="http://www.med.upenn.edu/apps/faculty/index.php/g275/p2328" style="color: magenta;">Carl June</a>, tested a novel therapy to help treat three individuals with chronic lymphocytic leukemia (CLL). The technique is an improvement in a molecular genetics technique called <a href="http://ghr.nlm.nih.gov/handbook/therapy/genetherapy"><b style="color: magenta;">gene therapy</b></a>. The principle behind gene therapy is to equip cells with a function that that particular cell didn’t have before. </span></div>
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<span style="font-size: small;">One of the first human-based study that gene therapy was used to treat babies born with severe combined immunodeficiency (SCID). SCID is named as such because people born with this genetic disease, have essentially no immune system making them incredibly susceptible to illnesses-think David Vetter aka “<a href="http://en.wikipedia.org/wiki/David_Vetter" style="color: magenta;">The Bubble Boy</a>”. One of the most common causes of SCID is a single genetic deficiency in a gene called adenosine deaminase (ADA). ADA is important in the building of new nucleotides for DNA synthesis, and as you might imagine, without this ADA enzyme, DNA synthesis ceases and without the ability to generate new strands of DNA, cells die when they divide. So ADA-deficiency largely affects highly proliferating cells, like your B and T cells. To treat ADA-deficiency, stem cells are isolated from the patient and sent to a laboratory, where the cells will be transduced with a viral vector. This virus is not immunogenic and is just used as a vector-something to deliver the ADA gene to the cell. Once the virus gets in, it will insert the ADA gene into the DNA of the isolated patient’s cell. The power of genetic therapy is great since what happens is “fixing” cells to express a necessary gene, like ADA, that the cells didn’t express before! Once the cells express ADA, they are transplanted back into the patient, where theoretically the person is cured of their genetic deficiency.</span></div>
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<span style="font-size: small;">However, there are many challenges to genetic therapy, which scientists have struggled with including: how to make the newly injected “fixed” cells last longer? These cells don’t seem to survive very long in the patient post transplantation, requiring patients to undergo this treatment over and over. Another concern is the lack of control of where the gene of interest inserts. For example, sometimes the gene is inserted in an unstable location, and cells lose the expression of the inserted gene over time. </span></div>
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<span style="font-size: small;">Since the early 1990’s when gene therapy was used to treat ADA-deficiency, researchers have used this genetic technique as a means to treat a variety of human diseases including Parkinson’s Disease, myeloid lymphoma, and HIV. With each trial, comes better understanding and innovations in perfecting the therapy to enhance its effectiveness.</span></div>
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<u><i><b><span style="font-size: small;">The Molecular Immunolog:</span></b></i></u><u><i><b><span style="font-size: small;">Re-engineering Our Immune System to Kill Cancer </span></b></i></u></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiiIg_OBHygyQi287vsRkPsJ6rzUjoegiHivElBMA8X6CXg1WNO_q5rrAzoF8lO9x3D0hZPZNftxtxm94sEa3n5dg3KMMPRLovL7mikGzGWHTd1KUdS95tpdjNm-hQX5wmuyZYwpjArmbA/s1600/chekmasova_no44_figure_1.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="287" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiiIg_OBHygyQi287vsRkPsJ6rzUjoegiHivElBMA8X6CXg1WNO_q5rrAzoF8lO9x3D0hZPZNftxtxm94sEa3n5dg3KMMPRLovL7mikGzGWHTd1KUdS95tpdjNm-hQX5wmuyZYwpjArmbA/s400/chekmasova_no44_figure_1.jpg" style="cursor: move;" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;">Creating Chimeric Antigen Receptors (CARs) by piecing together signaling components from different proteins using molecular biology. CART19 would look similar with the anti-tumor extracellular domain to recognize CD19 with the intracellular TCR signaling domain.</span><span class="Apple-style-span" style="font-size: xx-small;"> From</span><span class="Apple-style-span" style="color: magenta; font-size: xx-small;"><a href="http://www.blogger.com/goog_489642367"> </a><a href="http://www.blogger.com/goog_489642367"></a></span><a href="http://www.discoverymedicine.com/Alena-A-Chekmasova/2010/01/22/adoptive-t-cell-immunotherapy-strategies-for-the-treatment-of-patients-with-ovarian-cancer/" style="font-size: x-small;"><span id="goog_489642365" style="color: magenta;">DiscoveryMagazine.com</span><span id="goog_489642366" style="color: black;"></span></a></td></tr>
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<span style="font-size: small;"> The new study, published in two parts by June’s group in <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1103849?query=TOC#t=abstract"><i style="color: magenta;">TheNew England Journal of Medicine</i></a> and <a href="http://stm.sciencemag.org/content/3/95/95ra73.full"><i style="color: magenta;">Science TranslationalMedicine</i></a>, provide novel innovations to gene therapy as a potential treatment of CLL. CLL is a form of cancer in which B cells grow out of control and form tumors. <b style="color: magenta;">The goal of June’s latest published research was to figure out a way for a patient’s own body to find the B cell tumor and kill it.</b> Sounds pretty bizarre and extremely hopeful right? It doesn’t seem so unreal when you begin to think of how your body fights off other harmful agents. When pathogenic bacteria infect you, for example, your immune cells are able to detect the bacteria and recognize it as foreign. In a matter of a few days your immune system is fully activated, innate cells are being rapidly recruited to the site of infection and sending signals to the rest of your body to alert that an infection is occurring. Meanwhile your T cells become activated and divide like crazy and migrate rapidly to the site of infection to help exterminate the bacteria. In addition, some of these responsive T cells live essentially forever as <u style="background-color: magenta;"><b>memory T cells</b></u>, so that if and when that same bacteria infects you, you are better prepared with T cells that remember that bacteria and kill it more quickly than the first time. </span></div>
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<span style="font-size: small;">If you apply this same concept to eradicating a cancerous tumor, by having T cells that could recognize tumor cells and kill them, you could develop a therapy that would lessen the requirement of using painful chemicals and drugs to solely fight cancer and circumvent rejection issues since the treatment is using the patient’s own cells to kill the tumor (versus bone marrow transplant from another person, where graft-verse-host disease is a possible danger).</span></div>
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<span style="font-size: small;"> So how did June and his research team do this? They engineered a gene-construct in the lab consisting of an extracellular domain that recognizes a protein only expressed by B cells (CD19) fused to an intracellular signaling component of the T cell receptor (TCR). With this strategy, T cells would be able to recognize B cells, become activated, proliferate, and subsequently kill their targeted B cell. This sort of genetic engineering is a forte of June’s laboratory and is called <b><u><span style="background-color: magenta; color: black;">chimeric antigen receptor (CAR) generation</span>.</u> </b>The clinical trial was appropriately titled "CART19" (CAR+ T cells for CD19). </span></div>
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<span style="font-size: small;"> By transducing the CLL patients’ isolated T cells with a viral vector containing this CAR, then injecting these CAR+ cells into the CLL patients, they found that the<span style="color: magenta;"> “</span><b style="color: magenta;">engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months …moreover, a portion of these cells persisted as memory CAR+ T cells…</b><span style="color: magenta;">”</span><span style="color: magenta;"> </span> The authors of the study explain that these memory B-cell reactive T cells “may provide a mechanism for CAR memory by means of “self-vaccination/boosting” and, therefore, long-term tumor immunosurveillance”! This exciting research really puts forth the idea that we are on the right track to discovering the ultimate treatment for cancer patients- a treatment that consists of as little pain, money and tumor re-occurrence as possible. <b style="color: magenta;">Utilizing the body’s own defense system to fight cancer, with the potential ability to fight the tumor over and over again without further injections and drugs, may represent an ideal cancer therapy!</b></span><br />
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<span style="font-size: small;">The patients who participated in this study all had “advanced, chemotherapy-resistant CLL”. <b style="color: magenta;">Two of three patients in the study are in remission 10 months post CART19 infusion; the third still has the disease.</b> The researchers acknowledge that chemotherapy still plays in a role in fighting tumors, and that chemo is likely to have played a role in the success of their CART19 therapy. It is important to consider, that this research-however exciting-is still in the very early stages of development and much is left unknown including: 1) how long these CAR+ memory T cells live for and if their effector function is still in tact, 2) how healthy B cells are affected by this therapy, since the targeted protein, CD19, is expressed by all B cells-tumor and healthy ones and 3) if there are any long-term side effects of using the particular virus vector used in this study. Importantly, all three CART19 patients are still being monitored to further address these questions.</span></div>
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<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_white.png" style="border-bottom-width: 0px; border-color: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px;" /></a></span>
<span class="Z3988" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Science+translational+medicine&rft_id=info%3Apmid%2F21832238&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=T+cells+with+chimeric+antigen+receptors+have+potent+antitumor+effects+and+can+establish+memory+in+patients+with+advanced+leukemia.&rft.issn=1946-6234&rft.date=2011&rft.volume=3&rft.issue=95&rft.spage=&rft.epage=&rft.artnum=&rft.au=Kalos+M&rft.au=Levine+BL&rft.au=Porter+DL&rft.au=Katz+S&rft.au=Grupp+SA&rft.au=Bagg+A&rft.au=June+CH&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Cancer%2C+Clinical+Research%2C+Pharmacology%2C+Physiology%2C+Genetics">Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, & June CH (2011). T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. <span style="font-style: italic;">Science translational medicine, 3</span> (95) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21832238" rev="review"><span class="Apple-style-span" style="color: magenta;">21832238</span></a></span><br />
<a href="http://www.researchblogging.org/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_white.png" style="border-bottom-width: 0px; border-color: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px;" /></a><span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+New+England+journal+of+medicine&rft_id=info%3Apmid%2F21830940&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Chimeric+antigen+receptor-modified+T+cells+in+chronic+lymphoid+leukemia.&rft.issn=0028-4793&rft.date=2011&rft.volume=365&rft.issue=8&rft.spage=725&rft.epage=33&rft.artnum=&rft.au=Porter+DL&rft.au=Levine+BL&rft.au=Kalos+M&rft.au=Bagg+A&rft.au=June+CH&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Cancer%2C+Clinical+Research%2C+Pharmacology%2C+Physiology%2C+Genetics"></span><br />
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"> Porter DL, Levine BL, Kalos M, Bagg A, & June CH (2011). Chimeric antigen receptor modified T cells in chronic lymphoid leukemia. </span><span style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small; font-style: italic;">The New England journal of medicine, 365</span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif; font-size: x-small;"> (8), 725-33 PMID: </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/21830940" rev="review" style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><span class="Apple-style-span" style="color: magenta;">21830940</span></a>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com11tag:blogger.com,1999:blog-5699986821429190705.post-57916603707928897822011-08-05T05:20:00.000-07:002011-11-03T13:02:41.722-07:00Learning to live together: new research explains how bacteria's urge to survive in our gut promotes intestinal health<style>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: Georgia, 'Times New Roman', serif; font-size: xx-small;">Get to know your insides and the benefits to having a symbiotic relationship with the microbial world!</span><span style="font-size: xx-small;"> </span><span style="font-size: xx-small;"><a href="http://www.foodpoisonjournal.com/food-poisoning-information/increased-short-and-longterm-risk-of-inflammatory-bowel-disease-after-salmonella-or-campylobacter-g/" style="color: black;">From Food Poison Journal</a></span></td></tr>
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<b><u><i><span style="font-size: small;">Public Interest Note:</span></i></u></b></div>
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<span style="font-size: small;">The mere thought of <u><b style="background-color: magenta;">microbes</b></u>: bacteria, parasites, fungi and viruses tend to make us sick to our stomach. We all know that when we catch a cold: a virus is to blame and when we have a nasty skin rash, we apply creams to kill off the infection-causing bacteria. To think that our bodies are coated with an estimated 100 trillion microbial cells <sup>1</sup> can be, at first, a very startling and threatening idea to believe. 100 trillion is a ridiculously large number to conceptualize, but let’s try to put this number into perspective: it is estimated that our Milky Way Galaxy contains 200-400 billion stars.<sup> 2</sup> <b style="color: magenta;">For those of you keeping score at home, that’s about a ten-fold difference in that for every star in our night sky, there are ten times more microbes colonizing a single person’s body.</b><b><span style="color: magenta;"> </span><a href="http://www.nature.com/nature/journal/v464/n7285/full/nature08821.html#B1" style="color: magenta;">Yes, that’s right- that estimated 100 trillion microbial cells is for ONE person.</a><span style="color: magenta;"> </span></b> In addition, the number of microbial cells found in and on our body outnumbers our human cells 10:1. Needless to say, if we were to think of ourselves in terms of cellular content we would have to think of ourselves as being more microbial than human! Surprisingly, we know more about the stars millions of light years away than we do about the microbes living in and on our bodies!</span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgG_EFFB32h5JfY11l5uIuaQeX1FSRm5daW9b6Trcqh5IpKqLe7LxQ0GS6C0lyyMOaKJ6vEd2RkZk1UlEJHpzN6Jj2BtE0EsVmUqLJb_tJd6fNrRsUDpR903tqKI58YriNy9i79PRzH6X4/s1600/gut-population-1233311.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgG_EFFB32h5JfY11l5uIuaQeX1FSRm5daW9b6Trcqh5IpKqLe7LxQ0GS6C0lyyMOaKJ6vEd2RkZk1UlEJHpzN6Jj2BtE0EsVmUqLJb_tJd6fNrRsUDpR903tqKI58YriNy9i79PRzH6X4/s1600/gut-population-1233311.jpg" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-size: xx-small;">from <a href="http://neuroanthropology.net/"><span class="Apple-style-span" style="color: magenta;">neuroanthropology.net</span></a></span></td></tr>
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<span style="font-size: small;">Whew! It can be very exhausting concentrating on such big numbers! After all, this IS an immunology blog, not a mathematical one! Most of the microbes studied, thus being the ones that are best understood are the ones that cause severe diseases and make us sick. However, the number of these virulent bugs doesn’t come close to the number of non-disease causing microbes that live with us everyday. So why spend all our time and resources studying the things that we encounter rarely and that constitute a fraction of the total number of microbes we live with everyday? One major reason is because, in order to study a microbe, it has been historically crucial to be able to isolate it and study it in the lab. However, <u><b style="background-color: magenta;">commensal bacteria</b></u>, the microbes we live with that don’t cause disease, are very tricky bugs that don’t seem to cooperate with historical scientific practices. They are usually very difficult to isolate and grow in the lab with usual laboratory medias. One explanation for this is that the <b style="color: magenta;">microbial species living inside our bodies are part of a complex ecosystem (aka <u>microbiome/microbiota</u>)</b> that we do not fully understand yet, making it incredibly difficult to recreate in the lab and study. </span></div>
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<span style="font-size: small;">That is, until recently, when the National Institutes of Health launched a $140 million initiative in 2007 called <a href="https://commonfund.nih.gov/hmp/" style="color: magenta;">“The Human Microbiome Project (HMP)”. </a><span style="color: magenta;"> </span><a href="http://www.hmpdacc.org/impacts_health/impact_health.php" style="color: magenta;">Through a large cooperation of the Nation’s leading microbiology, genetics, bioinformatics and immunology laboratories,</a> the HMP mission is to generate “resources enabling comprehensive characterization of the human microbiota and analysis of its role in human health and disease”.<sup> 3</sup> The HMP has undoubtedly spearheaded the advancement of genomic sequencing strategies to better understand what kinds of microbes live on our skin, in our nose and mouth, gastro-intenstinal and urogenital tracts. With an enhancement of research technology advancement, and an increase in federal funding devoted to studying commensals, our understanding of our microbiome and how it relates to our overall health has greatly increased over the last couple years.</span></div>
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<span style="font-family: Arial;"> <span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">In fact, earlier this year, fascinating research led by Peer Bork’s group at the European Molecular Biology Laboratory in Germany, </span></span><span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><a href="http://www.nature.com/nature/journal/v473/n7346/full/nature09944.html#/functional-biomarkers-for-host-properties" style="color: magenta;">discovered that humans can be classified based on three distinct gut microbiomes.</a> <sup>4</sup> </span><br />
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">The research team analyzed genomic data obtained from human fecal matter (the least invasive (and least glamorous) method to analyze bacteria living in your guts) derived from people living in Denmark, France, Italy, Spain, Japan and the U.S. and discovered that three different clusters could be distinguished such that irregardless of sex, weight, height, age or geographic location, the balance of gut bacteria could be separated into 3 different groups-each differing in the bacterial contents that lived in their gut. People who were Type 1 had a different balance of gut bacteria than people in Type 2 or 3. Similar to bloodypes, that is that all people can be classified into one of 4 groups based on if they express A, B, AB or O antigens on their red blood cells, Bork suggests that this new biological classification, enterotypes (named for the collection of bacteria that live in the gut that distinguish the three groups) may be used to better tailor diets, drug regimines and antibiotics for an individual based on his/her microbiome. For example, someone of Enterotype 1 may respond better to particular antibiotics or diets than someone who is Enterotype 2 or 3. <b style="color: magenta;">However, this is still a hypothesis that requires more research, funding and public interest to better understand the differences between these enterotypes and whether specific enterotypes are found in other highly colonized areas of the body such as the urogenital tract and skin, and importantly: if different microbial environments in our bodies play a role in disease susceptibility or resistance.</b> </span></div>
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<u><i><b><span style="font-size: small;">Probiotics: The Immunology Behind the Health Buzz</span></b></i></u></div>
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<span style="font-size: small;">Most of the “microbial cosmos” living inside our body are bacteria, 70% of which take up residence in our digestive tract. <sup>5</sup> What are these bacteria doing there? Perhaps the best way to answer that question is think of what happens when these bacteria aren’t there. Researchers can discover answers to this question by using <b style="background-color: magenta;"><u>germ-free mice</u></b> to model what it would be like for humans without intestinal flora. To do this, mice are born via caesarian section and then immediately housed in a sterile environment by which all their bedding, cages, and food is autoclaved, preventing the colonization of any detectable bacteria. Studies using such mice have revealed these germ-free mice have increased susceptibility to infections, reduced digestive enzyme activity, muscle wall thickness, and decreased vascularity and nutrient uptake.<sup>6</sup> All of these observations are important for maintaining a healthy gut environment. That’s right: bacteria can be healthy for us! The commensal bacteria that constitute our intestinal microbiome largely include bacteria of the genera: <i>Bacteroides, Clostridium, Escherichia </i>and<i> Lactobacillus.</i> Some of these genera might seem familiar, most likely because you might know of a common species within these genera that are pathogenic like <i>Clostridium tetani</i> (causes tetanus) and <i>Escherichia coli</i> O157:H7 (common to foodborne illness). <b style="color: magenta;">It’s important to re-iterate that commensal bacteria are part of your normal gut flora that you are essentially born with, and are NOT pathogenic. </b></span></div>
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<span style="font-size: small;">Molecules expressed by commensal bacteria that stimulate their growth are known as <b style="background-color: white; color: magenta;">probiotics</b> (as opposed to antibiotics, which kill bacteria). Commensal bacteria express a variety of surface molecules that are an intense area of current research because of their potential to use these molecules to communicate to our cells-epithelial, neuron and immune cells to mediate their beneficial actions. The most commonly studied, and therefore advertised, are probiotics generated by <i>Lactobacilli</i>. <i>Lacto</i>-meaning milk, is how this bacteria generally gets into your gut, therefore making <i>Lactobacilli</i> easy to culture and use as a medicinal tool, since it lives in fermented milk such as yogurt and cheese. Probiotics, like <i>Lactobacilli</i> have been clinically studied for its ability to attenuate gastrointenstinal infections, allergic symptoms, inflammatory bowel disease (IBD), decrease colon cancer severity <sup>7</sup> and alterations in behavior including autism <sup>8</sup>. (Note: yogurts marketed specifically as “probiotic” contain enriched amounts of certain strains of priobiotic bacteria.) <b style="color: magenta;">There are three main ways in which bacteria can be beneficial to the health of our guts: </b></span></div>
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<span style="font-size: small;">1. Competing against invading pathogens by secreting antimicrobial peptides and lowering the gut pH</span></div>
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<span style="font-size: small;">2. Increasing barrier protection and mucus generation to protect our guts from pathogen invasion and enhancing nutrient acquisition</span></div>
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<span style="font-size: small;">3. <u style="background-color: magenta;"><b>Immunomodulation</b></u> by affecting gut immune cells function and distribution.</span></div>
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<span style="font-size: small;"> For example, <i>Lactobacillus acidophilus</i> has been reported to inhibit pathogenic E. coli-induced inflammatory cytokine release by intestinal epithelial cells (IECs). There is data to suggest that this happens due to a molecule expressed by common Gram-positive bacteria, called lipoteichoic acid (LTA). It is thought that LTA, which looks structurally very similar to a molecule expressed by pathogenic bacteria, is able to outcompete and bind tighter to a receptor on IECs, thereby blocking inflammation. <sup>9</sup> Commensal bacteria have been shown to further induce an anti-inflammatory environment, by regulating the T and B cells, macrophages and dendritic cells in the intestines. For example, <i>Lactobacilli</i> induces the production of <b><span style="color: magenta;">the potent anti-inflammatory cytokine, IL-10</span>,</b> from dendritic cells and macrophages, while increases antibody secretion from B cells. <sup>10</sup> Although we generally know the beneficial effects of commensal bacteria, we don’t fully understand the biological mechanisms to explain <i>how</i> probiotic bacteria contribute to protection from such an array of diseases. </span></div>
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<span style="font-size: small;">In 2005, the Nobel Prize for Physiology and Medicine was awarded to Australian Physicians/Microbiologists, Robin Warren and Barry Marshall. Warren and Marshall discovered “the bacterium <i>Helicobacter pylori</i> and its role in gastritis and peptic ulcer disease”.<sup>11 </sup> Ann O’Hara and Fergus Shanahan recall the 2005 Nobel Prize and explain <b style="color: magenta;">one crucial key in unlocking the mystery of how priobiotics prevent disease, stating that this “is a reminder that the solution to some human diseases does not reside solely within the host but rather might be found at the interface with the microbial environment”</b>. <sup>12</sup></span><br />
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<u><i><b><span style="font-size: small;">Understanding Beneficial Bacteria: Why This Research Paper Matters</span></b></i></u></div>
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<span style="font-size: small;">Although the field of probiotic research is expanding, there remain many questions left unanswered including:</span></div>
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<span style="font-size: small;">1. Which molecules involved-expressed by both the bacteria and our immune cells? </span></div>
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<span style="font-size: small;">2. How are commensal bacteria beneficial to the maintenance of healthy gut?</span></div>
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<span style="font-size: small;">3. If bacteria express similar molecules, how does our immune system recognize the difference between commensal and pathogenic microbes? </span></div>
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<span style="font-size: small;">The answers to these questions are among the primary foci of a recent paper led by </span> <style>
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</style> <span style="color: magenta; font-size: small;"><a href="http://biology.caltech.edu/Members/Mazmanian"><span style="color: magenta; font-family: Georgia, 'Times New Roman', serif;">Sarkis Mazmanian’s</span></a><span style="font-family: Georgia, 'Times New Roman', serif;"> </span></span><span style="font-size: small;"> research group at California Institute of Technology. One of the many reasons why Mazmanian’s research is so interesting is because he unselfishly thinks about human disease from the perspective of the microbe. In fact it seems he tries to stand up for the little guys, explaining that, “They [the bacteria] couldn’t care less about us except that we provide them a stable and nutrient-rich habitat”. Mazmanian, whose primary research interest is to better understand why the “good” bacteria, the commensals, are good for us, believes that commensal bacteria are just trying to live another day in our guts, skin and mouth-and they can potentially evolve new ways to do this anyway they can, weather it be by preventing cancerous tumors to form, harsh inflammatory environments or pathogenic intruders from taking over their home. These beliefs represent a compelling juxtaposition between microbiologists and medical professionals. Most scientists studying immunology and medicine think of particular immunological phenomena from the perspective of the host (people) such that even though we know that some bacteria are good for us, they believe that we, the host, have evolved to live symbiotically with bacteria. But perhaps, thinking of this from an entirely human-centered perspective is not the only way to understand the fundamental question: how and why are commensal bacteria in our gut?</span></div>
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<span style="font-size: small;">Why not let Mazmanian explain in his own words the importance of investigating this bacteria-focused angle to help solve some the biggest concerns in human health?:</span></div>
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<span style="font-size: small;">Perhaps, it is this refreshing and novel outlook that enabled <span style="color: magenta;">Mazmanian to be named one of </span><a href="http://discovermagazine.com/2008/dec/20-best-brains-under-40" style="color: magenta;">Discover magazine’s “20 best brains under 40” in 2008</a>. In that interview, he reasons <b style="color: magenta;">“The potential of beneficial microbes appears to be limitless” and that “this symbiotic relationship between the human body and microbes [is] a gold mine of potential therapies for a number of illnesses”</b>.<sup> 13</sup> </span></div>
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<u><i><b><span style="font-size: small;">What the &*%$#! Does the Title Mean?!</span></b></i></u></div>
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<span style="font-size: small;">Round, JL., et al. <b><a href="http://www.sciencemag.org/content/332/6032/974.full" style="color: magenta;">“The Toll-LikeReceptor 2 Pathway Establishes Colonization by a Commensal of the HumanMicrobiota”. </a></b><i>Science</i>. 332:974-977. (2011).</span></div>
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<span style="font-size: small;">1. <b style="background-color: magenta; color: black;"><u>Toll-Like Receptors (TLRs)</u></b> are one of the most extensively studied, most important signaling molecules in immunology. They are named “Toll-<u>LIKE</u>”, because the first such receptor, Toll, was discovered in <i>Drosphilla</i>, a common fruit fly used as a model for genetics research. Originally identified as an important gene that regulated dorsoventral axis formation in developing embryos, a Toll-deficient fruit fly revealed that these flies were highly susceptible to fungal infections. Since that discovery, in the early 1990’s, Toll-Like receptors have been identified in every animal with an immune system. The signaling cascade and inflammatory output is amazingly similar between the fruit fly and humans, thus making the discovery of Toll one of the most intriguing examples of how basic research and the use of model organisms provide powerful insight into understanding human disease. </span><br />
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<tr><td class="tr-caption" style="text-align: center;">Great cartoon illustrating the function of TLRs as receptors on the surface of cells (TLR1/2,4,5,2/6) as well as within cells (TLR3,7,9) to detect microbial patterns not expressed by humans. Immune cells are particularly good at expressing these TLRs and using them to alert the body of infection. <b>But how do commensal microbes differ from pathogenic ones with respect to TLR activation? </b>This is the question that drives Mazmanian's research group. <span class="Apple-style-span" style="font-size: xx-small;">Image from <span class="Apple-style-span" style="color: magenta;"><a href="http://www.invivogen.com/">www.invivogen.com</a></span></span></td></tr>
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<span style="font-size: small;">In humans, there are at least 10 TLRs that are capable of recognizing unique molecules expressed exclusively by microbes, and not us. Examples of <b><u><span style="background-color: magenta;">microbial-associated molecular patterns (MAMPs)</span></u></b> include: lipopolysaccharide (LPS), flagellin, and single stranded RNA (ssRNA) which stimulate immune cells to become highly inflammatory. The inflammatory response is very quick and offers a way to recruit immune cells to the site of infection to destroy pathogens with speed. Like most biological processes, if there’s an “on” switch (pro-inflammation), there’s a regulatory “off” switch. Regulation is paramount to a functioning immune system and survival of a host, for example <a href="http://medical-dictionary.thefreedictionary.com/endotoxin+shock" style="color: magenta;">endotoxic shock</a> is caused by a significant dose of LPS, which is found on the surface of Gram-negative bacteria like the pathogenic strain, <i>Escherichia coli</i> O157:H7. The “shock” derives from an overproduction of inflammatory cytokines induced by TLR stimulation that mediates high fever, shortness of breath and even death. TLR4 is the TLR that recognizes LPS. </span></div>
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<span style="font-size: small;">The focus of the paper discussed below, is TLR2, which is known to bind primarily MAMPs associated with Gram-positive bacteria and yeast. TLR2 is expressed on the surface of nearly every immune cell and has also been detected on epithelia. <sup>14</sup> However, a few years ago it was discovered that a MAMP located on the Gram-negative bacteria, <i style="color: black;">Bacteroides fragilis</i> called <b style="color: magenta;"><u>polysaccharide A (PSA)</u></b> can also stimulate TLR2. Usually, it isn’t terribly exciting news to read: “bacteria activate TLR!”; however things began to turn into a more thrilling adventure when you learn that this is a commensal bacteria that belongs to the genera,<b><u> </u><i style="color: magenta;">Bacteroides</i><span style="color: magenta;">, which alone makes up 30% of your gut bacterial flora.</span><u> </u></b>Currently, we do not fully understand why B. fragilis expresses a molecule that binds TLRs-but we do know that purified PSA can regulate the inflammatory cytokine release by T cells and dendritic cells <sup>15</sup> and we know that purified PSA injected into mice, can prevent the onset of inflammatory bowel disease (IBD). <sup>16</sup></span></div>
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<span style="font-size: small;">Both of these findings are very interesting, but one of the most critical aspects to support these phenomena remains unknown: <b style="color: magenta;">if, according to Mazmanian commensal bacteria don’t give a damn about us; that they are living with us because we let them, why does <i>B. fragilis</i> express PS? Does PSA/TLR2 signaling do something positive for the bacteria, in addition to comforting us with a balanced gut? </b></span><br />
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<span style="font-size: small;"><u><i><b>Now, with the information above, we can infer:</b></i></u> </span></div>
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<span style="font-size: small;"> This paper will provide data regarding <b style="color: magenta;">PSA as being beneficial to, <i>B. fragilis</i> because of its interaction with TLR2 allowing the commensal bacteria to survive and colonize in our gut, while regulating out intestinal inflammatory environment.</b></span></div>
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<u><i><b><span style="font-size: small;">Ready for an adventure? Read on for a guided-tour through the scientific data!</span></b></i></u><br />
<span style="font-family: Arial;"> <span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;"> In this paper, the basic question that motivates Round and colleagues’ research is this: </span><b style="font-family: Georgia,"Times New Roman",serif;"><span style="color: magenta;">why don’t commensal bacteria activate an inflammatory immune response, but pathogenic bacteria do, given the fact that both express MAMPs that stimulate TLRs?</span> </b><span style="font-family: Georgia, 'Times New Roman', serif;">Given that this research is directed by Mazmanian, the team set out to investigate this question with the hypothesis that </span><i style="font-family: Georgia,"Times New Roman",serif;">B. fragilis,</i><span style="font-family: Georgia, 'Times New Roman', serif;"> evolved ways to block our inflammatory, anti-microbial defense system so that this symbiotic bacteria can essentially go unnoticed by our gut’s immune system.</span></span><span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"> </span></span><br />
<span style="font-family: Arial;"><span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;"> To begin, they looked at inflammatory T cells in the gut. But not just any T cell (that’s right, there are at least 5 different subsets), they assessed a subset of T cells called, </span><b style="font-family: Georgia,"Times New Roman",serif;"><u><span style="background-color: magenta;">Th17 cells</span>, </u></b><span style="font-family: Georgia, 'Times New Roman', serif;">which populate the gut in response to infection and further the inflammatory immune response by produces loads of the inflammatory cytokine, IL-17. In the gut of wild-type (WT) mice, they found that Th17 cells constituted 7.65%. Interestingly, the germ-free mice only had about a tenth of Th17 cells compared to WT. This result indicates that total lack of commensal bacteria (germ-free mice) results in less inflammatory Th17 cells in the gut. But, when they mono-colonized germ-free mice with only </span><i style="font-family: Georgia,"Times New Roman",serif;">B. fragilis</i><span style="font-family: Georgia, 'Times New Roman', serif;">, so that the only bacteria living in these mice is this particular commensal, they found that the Th17 population increases slightly to 1.46%, and that when they genetically delete the PSA gene from </span><i style="font-family: Georgia,"Times New Roman",serif;">B. fragilis</i><span style="font-family: Georgia, 'Times New Roman', serif;">, the percent of Th17 cells in the gut increases dramatically to levels similar to that found in WT mice! This data suggests that </span><i style="font-family: Georgia,"Times New Roman",serif;">B. fragilis</i><span style="font-family: Georgia, 'Times New Roman', serif;"> is a relatively weak inducer of Th17 development since these germ-free mice colonized with </span><i style="font-family: Georgia,"Times New Roman",serif;">B. fragilis</i><span style="font-family: Georgia, 'Times New Roman', serif;"> has nearly 7 times less inflammatory T cells in their gut and that more importantly, by deleting PSA, </span><i style="font-family: Georgia,"Times New Roman",serif;">B. fragilis</i><span style="font-family: Georgia, 'Times New Roman', serif;"> looks like a pathogenic bacteria able to greatly induce Th17 development! Collectively, </span><b style="font-family: Georgia,"Times New Roman",serif;"><span style="color: magenta;">this data indicates that </span><i style="color: magenta;">B. fragilis</i><span style="color: magenta;"> actively blocks inflammatory Th17 development in the gut by expressing PSA!</span> </b><span style="font-family: Georgia, 'Times New Roman', serif;">I’d say that is one pretty impressive start to a paper! Let’s see what else they show us!</span></span></span><br />
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</style> <span style="font-family: Arial; font-size: 12pt;"><span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;">Next, Round, et al. set out to determine the mechanism by which PSA suppresses Th17 development. It is widely known in the T cell field, that the anti-inflammatory cytokine, IL-10, is a potent inhibitor of inflammatory T cells such as Th17. Also, based on their previously published research, that PSA limits IBD inflammation and that PSA can bind TLR2, the team wanted to know if TLR2 stimulation by PSA results in IL-10 production from immune cells. As mentioned before, a number of cells express TLR2, but since they are looking in the gut-where else better to start than investigating T helper cells and dendritic cells (DCs), which are among the most numbered immune cells in the gut? In an in vitro experiment, in which purified T cells are mixed together with cultured DCs and stimulated with purified PSA, IL-10 is produced. But where is the IL-10 coming from: the T cell or dendritic cell? To answer this question, the researchers repeated this in vitro experiment, using DCs from WT mice and T cells (CD4+, T helper cells) from TLR2-deficient mice. When they cultured these cells with PSA, IL-10 production was significantly reduced. To be thorough, they also performed a co-culture experiment with WT T cells and TLR2-deficient DCs stimulated with PSA. Under these conditions, the amount of IL-10 detected was just as high as in the presence of WT T cells and WT DCs, suggesting that</span></span> </span> <span style="font-size: small;"> <b><span style="color: magenta;">PSA was selectively stimulating TLR2 on T cells, not DCs, to induce IL-10 production!</span> </b>Even more interesting, is that DCs aren’t even needed to get PSA-induced IL-10 secretion; that T cells can recognize PSA via TLR2 and make IL-10 intrinsically! </span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiykcGSlKQhyphenhyphenT54gL5LTLMFmOoJ6Wa0-fUFURrCMZjBvWnvFkIn9KMPa5pOENEjCrm_tfUtCFGM41u9Fdo2P6VtTsTDnzRoRXqpTGbSCFiahtW2_Fa5P1N7gddrvpTJFtZEotU5gvwJZ7I/s1600/16448.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiykcGSlKQhyphenhyphenT54gL5LTLMFmOoJ6Wa0-fUFURrCMZjBvWnvFkIn9KMPa5pOENEjCrm_tfUtCFGM41u9Fdo2P6VtTsTDnzRoRXqpTGbSCFiahtW2_Fa5P1N7gddrvpTJFtZEotU5gvwJZ7I/s1600/16448.png" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">This diagram represents the "old" model of how B. fragilis regulated gut inflammation. From Mazmanian's newest research, we no know that <b>PSA can DIRECTLY induce Treg development by stimulating TLR2 on T cells, </b>thus by-passing the requirement for DCs to process and present antigen to T cells!! <br />
<span class="Apple-style-span" style="font-size: xx-small;">From <a href="http://www.rndsystems.com/"><span class="Apple-style-span" style="color: magenta;">www.rndsystems.com</span></a></span></td></tr>
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<span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span> With this data, they wanted to go back and see if TLR2 is the missing link to explain how PSA blocks Th17 development in the gut, as shown in Figure 1. When they mono-colonize germ-free mice that lack TLR2, with either the WT <i>B. fragilis</i> strain or the one without PSA, Th17 development is not impaired suggesting that TLR2 is critical to the mechanism by which <i>B. fragilis</i> is able to prevent inflammation in the gut! </span><br />
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<span style="font-size: small;"> Now the ultimate inquiry: So what?! It’s cool to discover the details that explain how commensal bacteria can regulate gut inflammation, but from Mazmanian’s perspective, microbes don’t care if our guts in a knot, making us want to cry in pain. <b><span style="color: magenta;"> </span></b><b><span style="color: magenta;">So, why does </span><i style="color: magenta;">B. fragilis</i><span style="color: magenta;"> express a molecule that blocks inflammation? What is the benefit of expressing PSA to the bacteria?</span></b> </span><br />
<span style="font-size: small;"> To address this important question, Round and colleagues looked at microscopic images of colon sections to look for <i>B. fragilis</i>. Using confocal microscopy and 3D digital reconstruction imaging, they discovered microcolonies of the commensal closely associated with the host intestinal tissue. There was no <i>B. fragilis</i> found in the germ-free mice. Further more, when the mono-colonized mice with PSA-deficient <i>B. fragilis</i>, they could hardly find any microcolonies, and injecting purified PSA recovered the bacteria’s growth in the intestinal tissue! So <b style="color: magenta;">it appears that not only is PSA inhibits inflammation, which is good for us, but PSA is good for the bacteria, because <i>B. fragilis</i> needs it to survive in our guts!</b></span></div>
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<span style="font-size: small;"> The obvious follow-up question to this extraordinary finding is: how does inflammation affect commensal bacteria survival? With the first bits of data indicating that PSA-deficient <i>B. fragilis</i> can’t survive in mice and that Th17 cells increases dramatically in mice colonized with <i>B. fragilis</i> lacking PSA, Round, et al. wanted to know if IL-17 was the reason <b><u>why</u></b> <i>B. fragilis</i> evolved to express PSA. To test this theory, they mono-colonized mice with PSA-deficient <i>B. fragilis</i> and injected a blocking antibody to inhibit IL-17. <b style="color: magenta;">Only in the presence of the anti-IL-17 antibody, was the PSA-deficient <i>B. fragilis</i> able to colonize and live in the intestines</b><span style="color: magenta;">!</span> This research team finally unveiled the reasons why and how<i> B. fragilis</i> live mutualistically with us!</span><br />
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<span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span> Of course, this still plenty of biological investigation to be done in completely understanding the purpose of commensal bacteria. For example, is PSA a universally expressed molecule on all Gram-positive commensal bacteria, or is PSA specific to <i>B. fragilis</i>? Furthermore, how do other common commensals such as <i>Lactobacillus spp</i>. survive in our guts and is this TLR mediated? In terms of the immunological mechanism, it is still unclear how exactly IL-17 is anti-microbial, which would complete the story of why <i>B. fragilis </i>wants to inhibit IL-17 function. Lastly, it remains to be understood how TLR2, which binds pathogenic ligands to induce inflammation can also recognize PSA on <i>B. fragilis</i> to block inflammation. <b style="color: magenta;">How does TLR2 on our immune cells know the difference between MAMPs on pathogenic vs commensal bacteria? </b>It’s always good to leave a few unsolved mysteries at the end of a paper; it really keeps the field of immunology and microbiology exciting and interesting, right?!</span><br />
<span style="font-size: small;"> Lastly, it would be interesting to see if these same findings can be observed in humans. If this were to be true, <b style="color: magenta;">it is clear that this novel data may result in new therapies to treat an array of gut inflammatory conditions such as IBD, Crohn’s and Celiac Disease like taking PSA-supplements purified PSA to treat a number of diseases that plague thousands of Americans!</b><i> </i></span><br />
<span style="font-size: small;"><i>On a side note:</i> if you are interested reading some of the best critical scientific writing currently available, I suggest you click <a href="http://www.sciencemag.org/content/332/6032/974.full" style="color: magenta;">here</a><span style="color: magenta;"> </span>to read the paper for yourself! I was blown away by the clarity and philosophical spin in the concluding statements from </span><span class="Apple-style-span" style="font-size: small;">Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, & Mazmanian SK " The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota". <span style="font-style: italic;">Science (2011) </span>discussion:</span><br />
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<i><span style="font-size: small;">“It is historically believed that the micriobiota is excluded from the mucosal surface. However, certain symbiotic bacteria tightly adhere to the intestinal mucosa and thus immunologic ignorance may not explain why inflammation is averted by the microbiota. Our study provides new insight into the mechanims by which the immune system distinguished between pathogens and symbionts….On the basis of the importance of the microbiota to mammalian health, evolution appears to have created molecular interactions that engender host-bacterial mutualism. In conclusion, our findings suggest that animals are not “hard-wired” to intrinsically distinguish pathogens from symbionts, and that microbital-derived mechanisms have evolved to actively promte immunologic tolerance to symbtiotic bacteria. This concept suggests a reconsideration of how we define self versus nonself.”</span></i></div>
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<span style="font-size: small;">This conclusion reads like an English literature paper, not a scientific one and left me wanting to push myself, when it comes time for me to write an article about my own research; to discuss it in a captivating manner that speaks to both the academic research community as well as the interested general public.</span><br />
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<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png" style="border: 0;" /></a></span>
<span class="Z3988" style="font-size: x-small;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Science+%28New+York%2C+N.Y.%29&rft_id=info%3Apmid%2F21512004&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Toll-like+receptor+2+pathway+establishes+colonization+by+a+commensal+of+the+human+microbiota.&rft.issn=0036-8075&rft.date=2011&rft.volume=332&rft.issue=6032&rft.spage=974&rft.epage=7&rft.artnum=&rft.au=Round+JL&rft.au=Lee+SM&rft.au=Li+J&rft.au=Tran+G&rft.au=Jabri+B&rft.au=Chatila+TA&rft.au=Mazmanian+SK&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Aging%2C+Cancer%2C+Cardiovascular%2C+Clinical+Research%2C+Pharmacology%2C+Physiology%2C+Genetics%2C+Pathology%2C+Metabolism%2C+Hematology">Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, & Mazmanian SK (2011). The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. <span style="font-style: italic;">Science (New York, N.Y.), 332</span> (6032), 974-7 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21512004" rev="review"><span class="Apple-style-span" style="color: magenta;">21512004</span></a></span><br />
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<b><i><span style="font-size: x-small;">References and Further Reading:</span></i></b><span style="font-size: x-small;"> </span><br />
<span style="font-size: x-small;">1: Qin, J., et al. “<a href="http://www.nature.com/nature/journal/v464/n7285/full/nature08821.html#B1" style="color: magenta;">A human gut microbial gene catalogue established by metagenomic sequencing</a>”. <i>Nature</i>. 464:59-65. (2010).</span></div>
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>2: Grant, Jo and Ben Lin. “<a href="http://members.nova.org/~sol/chview/chv5.htm" style="color: magenta;">The stars of the Milky Way</a>”. <i>ChView</i>.</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>3. The NIH Common Fund. “<a href="https://commonfund.nih.gov/hmp/overview.aspx" style="color: magenta;">The Human Microbiome Project: Overview</a>”. </span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>4: Arumugam, M., et al. “<a href="http://www.nature.com/nature/journal/v473/n7346/full/nature09944.html" style="color: magenta;">Enterotypes of the human gut microbiome</a>”. <i>Nature</i>. 473:174-180. (2011).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>5: Tlaskalova-Hogenova, H., et al. “<a href="http://www.nature.com/cmi/journal/v8/n2/full/cmi201067a.html" style="color: magenta;">The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune disease and cancer: contribution of germ-free and gnotobiotic animal models of human diseases</a>”. <i>Cellular & Molecular Immunology</i>. 8:110-120. (2011).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>6: Hentschel, U., et al. “<a href="http://www.sciencedirect.com/science/article/pii/S0966842X03000386" style="color: magenta;">Commensal bacteria make a difference</a>”. <i>Trends in Microbiology</i>. 11:148-150. (2003).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>7: Mohamadzadeh, M. et al. “<a href="http://www.pnas.org/content/108/suppl.1/4623.full" style="color: magenta;">Regulation of induced colonic inflammation by Lactobacillus acidophilus deficient in lipoteichoic acid</a>”. <i>PNAS</i>. 108:4623-4630. (2011).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>8: Heijtz, RD., et al. “<a href="http://www.pnas.org/content/108/7/3047.short" style="color: magenta;">Normal gut microbiota modulates brain development and behavior</a>”. <i>PNAS</i>. 108:3047-3052.(2011).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>9: Vidal, K., et al “<a href="http://www.ncbi.nlm.nih.gov/pubmed/11895971" style="color: magenta;">Lipoteichoic acids <i>from Lactobacillus johnsonii</i> strain La1 and <i>Lactobacillus acidphilus</i> strain La10 antagonize the responsiveness of human intestinal epithelial HT29 cells to lipopolysaccharide and gram-negative bacteria</a>”. <i>Infect. Immun.</i> 70: 2057-2064. (2002).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>10: Ng, SC., et al “<a href="http://www.ncbi.nlm.nih.gov/pubmed/18626975" style="color: magenta;">Mechanisms of action of probiotics: recent advances</a>”. <i>Inflamm. Bowel Dis</i>. 15:300-310. (2009).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>11: The Nobel Assembly. “<a href="http://nobelprize.org/nobel_prizes/medicine/laureates/2005/press.html" style="color: magenta;">Press Release: The Nobel Prize in Physiology or Medicine for 2005</a>”. Released on-line Oct. 3, 2005.</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>12: O’Hara, AM and Shanahan, F. “<a href="http://www.nature.com/embor/journal/v7/n7/full/7400731.html" style="color: magenta;">The gut flora as a forgotten organ</a>”. <i>EMBO</i>. 7:688-693. (2006).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>13: Grant, A., et al. “<a href="http://discovermagazine.com/2008/dec/20-best-brains-under-40" style="color: magenta;">20 Best Brains Under 40</a>”. <i>Discover</i>. Published online Nov. 20, 2008.</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>14: Wang, Q., et al. “<a href="http://jem.rupress.org/content/203/13/2853.abstract" style="color: magenta;">A bacterial carbohydrate links innate and adaptive responses through Toll-like receptor 2</a>”. <i>J. Exp. Med</i>. 203:2853-2863. (2006).</span><br />
<span style="font-size: x-small;"><span style="font-family: Georgia, 'Times New Roman', serif;"></span>15: Mazmanian, SK., et al. “<a href="http://www.nature.com/nature/journal/v453/n7195/abs/nature07008.html" style="color: magenta;">A microbial symbiosis factor prevents intestinal inflammatory disease</a>”. <i>Nature</i>. 453:620-625. (2008).</span><br />
<u><i><b><span style="font-size: small;"><br />
</span></b></i></u></div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com10tag:blogger.com,1999:blog-5699986821429190705.post-79493294419893294992011-07-07T12:10:00.000-07:002011-10-28T10:33:38.976-07:00On human health, interesting the public, and good scientific journalism...<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTmUNKcqw2OAX70hVVaK_qfmjAelRCQIMU64UeLAl2q9hdBDgmJoz-L7JKVvzioozfEJlw5Zvl84NuGOmmrm4_bVVanGzlGBSrlXwFt0MzJ28S45Jc_4N9n3d_HEX8ayqfM9CD4c_Ylls/s1600/ScienceJournalism1.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="135" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTmUNKcqw2OAX70hVVaK_qfmjAelRCQIMU64UeLAl2q9hdBDgmJoz-L7JKVvzioozfEJlw5Zvl84NuGOmmrm4_bVVanGzlGBSrlXwFt0MzJ28S45Jc_4N9n3d_HEX8ayqfM9CD4c_Ylls/s400/ScienceJournalism1.gif" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">from <a href="http://evidencebasedliving.human.cornell.edu/" style="color: black;">http://evidencebasedliving.human.cornell.edu/</a></span></td></tr>
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<span style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">In addition to the "pulled from the scientific journal headlines" research discussed here, I thought it would be interesting to periodically showcase fascinating research that I read </span></span><span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;">elsewhere. Awesome and interesting research about human health, disease and immunology is everywhere and <i>sometimes</i>, it's written about in a way that is clear, accurate and easy to understand! That last point is exactly what <b style="background-color: magenta;"><u>Escaping Anergy</u></b> is all about: a place to see, interpret, discuss and most importantly-UNDERSTAND- the scientific data behind the science stories we read about, the diseases we encounter and the medicines we take!</span></span><br />
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<span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;">Today I came across a story published in </span><i style="font-family: Georgia,"Times New Roman",serif;">The New York Times</i><span style="font-family: Georgia, 'Times New Roman', serif;"> written by Laura Beil entitled: </span><a href="http://www.blogger.com/goog_109663699" style="color: magenta; font-family: Georgia,"Times New Roman",serif;">"In eyes, a clock calibrated by wavelengths of light".</a><a href="http://www.nytimes.com/2011/07/05/health/05light.html?bl" style="color: magenta; font-family: Georgia,"Times New Roman",serif;"> </a><span style="font-family: Georgia, 'Times New Roman', serif;">It seemed apropos for me to include this </span><i style="font-family: Georgia,"Times New Roman",serif;">NYT</i><span style="font-family: Georgia, 'Times New Roman', serif;"> article after just posting about </span><a href="http://escapinganergy.blogspot.com/2011/07/why-are-you-getting-sick-even-with.html" style="color: magenta; font-family: Georgia,"Times New Roman",serif;">new data indicating a role for sleep in boosting vaccine efficiency</a><span style="font-family: Georgia, 'Times New Roman', serif;">! Beil briefly, but accurately discusses the research from the University of Basel regarding how</span><span style="color: magenta; font-family: Georgia, 'Times New Roman', serif;"> </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/21415172" style="color: magenta; font-family: Georgia,"Times New Roman",serif;">blue light (the kind strongly emitted by LED TVs, laptops, etc) enhances our alertness while inhibiting our ability to become sleepy.</a><span style="color: magenta; font-family: Georgia, 'Times New Roman', serif;"> </span><span style="font-family: Georgia, 'Times New Roman', serif;"> In short, this happens because blue light (compared to reddish/orange light like older incandescent light bulbs) slows the production of melatonin, a light-sensitive hormone that induces sleep and is critical for the maintenance of circadian rhythm (why we humans sleep at night and are awake when it's light). Biel also discusses how this new data may play a role understanding cancer progression and infection susceptibility as people are increasingly tied to electronic devices that utilize blue light. </span></span><br />
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<span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;">The lead author on this paper, Christian Cajochen, is the head for the Center for Chronobiology at the University of Basel and a quick <a href="http://www.ncbi.nlm.nih.gov/pubmed/" style="color: magenta;">pubmed</a> search reveals that he also recently published in </span><i style="font-family: Georgia,"Times New Roman",serif;">Proceedings of the National Sciences (PNAS)</i><span style="font-family: Georgia, 'Times New Roman', serif;"> regarding the </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/21482780" style="color: magenta;"><span style="font-family: Georgia, 'Times New Roman', serif;">role of serum proteins in regulating the circadian rhythms of fibroblasts (cells that are important in wound healing and disease)! </span><span style="color: black;"></span></a><span style="font-family: Georgia, 'Times New Roman', serif;">Although they still don't know which protein(s), the most common in serum include: antibodies, complement (important in killing invading microbes), and albumin, it is very exciting learning that our immune system is tightly connected with nearly every physiological process including sleep and circadian rhythm maintenance!</span></span><br />
<span style="font-size: small;"><br style="font-family: Georgia,"Times New Roman",serif;" /><span style="font-family: Georgia, 'Times New Roman', serif;">The idea that light affects the way we sleep and that sleep can in turn modulate disease is not a new revelation, however what remains to be clear is <i>HOW</i> exactly this all happens. The more we research, the more we will understand the underlying mechanisms that control human disease (progression, susceptibility, and host defense ability). The role of sleep and light is just now becoming of interest in the immunology and medical research fields, with many intriguing findings! It's exciting to live in a time when there's so much quality and new research available for the public to learn about and discuss! </span></span><br />
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<span style="font-size: small;"><span style="font-family: Georgia, 'Times New Roman', serif;">What's a great science-related story you've read about recently? What kind of research would you like to see more of discussed on Escaping Anergy? I appreciate all your comments and suggestions! Thanks for reading!</span></span>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+applied+physiology+%28Bethesda%2C+Md.+%3A+1985%29&rft_id=info%3Apmid%2F21415172&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Evening+exposure+to+a+light-emitting+diodes+%28LED%29-backlit+computer+screen+affects+circadian+physiology+and+cognitive+performance.&rft.issn=8750-7587&rft.date=2011&rft.volume=110&rft.issue=5&rft.spage=1432&rft.epage=8&rft.artnum=&rft.au=Cajochen+C&rft.au=Frey+S&rft.au=Anders+D&rft.au=Sp%C3%A4ti+J&rft.au=Bues+M&rft.au=Pross+A&rft.au=Mager+R&rft.au=Wirz-Justice+A&rft.au=Stefani+O&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CResearch+%2F+Scholarship%2CImmunology%2C+Aging%2C+Clinical+Research%2C+Physiology+%2C+Science+Communication"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+applied+physiology+%28Bethesda%2C+Md.+%3A+1985%29&rft_id=info%3Apmid%2F21415172&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Evening+exposure+to+a+light-emitting+diodes+%28LED%29-backlit+computer+screen+affects+circadian+physiology+and+cognitive+performance.&rft.issn=8750-7587&rft.date=2011&rft.volume=110&rft.issue=5&rft.spage=1432&rft.epage=8&rft.artnum=&rft.au=Cajochen+C&rft.au=Frey+S&rft.au=Anders+D&rft.au=Sp%C3%A4ti+J&rft.au=Bues+M&rft.au=Pross+A&rft.au=Mager+R&rft.au=Wirz-Justice+A&rft.au=Stefani+O&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CResearch+%2F+Scholarship%2CImmunology%2C+Aging%2C+Clinical+Research%2C+Physiology+%2C+Science+Communication"><br /></span></span><br />
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+applied+physiology+%28Bethesda%2C+Md.+%3A+1985%29&rft_id=info%3Apmid%2F21415172&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Evening+exposure+to+a+light-emitting+diodes+%28LED%29-backlit+computer+screen+affects+circadian+physiology+and+cognitive+performance.&rft.issn=8750-7587&rft.date=2011&rft.volume=110&rft.issue=5&rft.spage=1432&rft.epage=8&rft.artnum=&rft.au=Cajochen+C&rft.au=Frey+S&rft.au=Anders+D&rft.au=Sp%C3%A4ti+J&rft.au=Bues+M&rft.au=Pross+A&rft.au=Mager+R&rft.au=Wirz-Justice+A&rft.au=Stefani+O&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CResearch+%2F+Scholarship%2CImmunology%2C+Aging%2C+Clinical+Research%2C+Physiology+%2C+Science+Communication">Cajochen C, Frey S, Anders D, Späti J, Bues M, Pross A, Mager R, Wirz-Justice A, & Stefani O (2011). Evening exposure to a light-emitting diodes (LED)-backlit computer screen affects circadian physiology and cognitive performance. <span style="font-style: italic;">Journal of applied physiology (Bethesda, Md. : 1985), 110</span> (5), 1432-8 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21415172" rev="review"><span class="Apple-style-span" style="color: magenta;">21415172</span></a></span>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com12tag:blogger.com,1999:blog-5699986821429190705.post-83344623032619890112011-07-05T15:06:00.000-07:002011-11-03T12:34:44.069-07:00How to get the most out of your next vaccine? A full night's sleep may enhance protection against viral infections<div class="separator" style="clear: both; text-align: center;">
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">from <a href="http://gabby22197.glogster.com/"><span class="Apple-style-span" style="color: magenta;">gabby22197.glogster.com</span></a></span></td></tr>
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<span style="font-size: small;"><i><b><u>Public Interest Note:</u></b></i></span></div>
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<span style="font-size: small;">Let’s begin with a simple question: Why do we sleep? To answer this, we can think of what happens when we don’t get enough or any sleep. The day after a sleepless night, often we feel irritable, exhausted, unhappy and stressed. If you are a parent, have a full-time job or a fellow graduate student you are acutely familiar with how precious even a few hours of sleep can be in redeeming your sense of sanity. The side effects of sleep can become dangerous when the actions of a sleep-deprived individual affect those around him/her. In March, <a href="http://www.blogger.com/Public%20Interest%20Note:%20Let%E2%80%99s%20begin%20with%20a%20simple%20question:%20Why%20do%20we%20sleep?%20%20To%20answer%20this,%20we%20can%20think%20of%20what%20happens%20when%20we%20don%E2%80%99t%20get%20enough%20or%20any%20sleep.%20%20The%20day%20after%20a%20sleepless%20night,%20often%20we%20feel%20irritable,%20exhausted,%20unhappy%20and%20stressed.%20%20If%20you%20are%20a%20parent,%20have%20a%20full-time%20job%20or%20a%20fellow%20graduate%20student%20you%20are%20acutely%20familiar%20with%20how%20precious%20even%20a%20few%20hours%20of%20sleep%20can%20be%20in%20redeeming%20your%20sense%20of%20sanity.%20%20The%20side%20effects%20of%20sleep%20can%20become%20dangerous%20when%20the%20actions%20of%20a%20sleep-deprived%20individual%20affect%20those%20around%20him/her.%20%20In%20March,%20an%20air%20traffic%20controller%20at%20Ronald%20Reagan%20Washington%20Airport%20fell%20asleep%20on%20the%20job,%20leaving%20two%20planes%20alone%20in%20the%20sky%20trying%20to%20land%20the%20planes%20alone.1%20Fortunately,%20in%20this%20case,%20no%20one%20was%20terrible%20injured,%20but%20the%20news%20magnified%20the%20public%E2%80%99s%20awareness%20and%20outrage%20of%20having%20to%20depend%20on%20sleep-deprived%20individuals%20for%20our%20safety.%20%20It%E2%80%99s%20not%20surprising%20the%20single%20air%20traffic%20controller%20fell%20asleep%20on%20the%20job%20since%20it%20was%20reported%20this%20was%20%E2%80%9Chis%20fourth%20consecutive%20overnight%20shift,%20which%20runs%20from%2010%20p.m.%20to%206%20a.m.%E2%80%9D%201%20In%20fact,%20the%20American%20Academy%20of%20Sleep%20Medicine%20International%20Classification%20of%20Sleep%20Disorders%20classifies%20this%20condition%20as%20Shift%20Work%20Sleep%20Disorder%20%28SWSD%29.%20SWSD%20plagues%20nearly%2070%%20of%20the%2015%20million%20Americans%20who%20work%20shifts%20between%2010%20p.m.%20and%206%20a.m.2%20%20%20It%20is%20further%20estimated%20that%20sleep%20deprived%20workers%20cost%20U.S.%20businesses%20$18%20billion%20a%20year.3%20%20%20Importantly,%20sleepiness%20does%20not%20only%20affect%20the%20people%20who%20work%20the%20%E2%80%9Cgraveyard%20shift%E2%80%9D,%20but%20in%20an%20increasingly%20fast-paced%20society,%20coupled%20with%20a%20tough%20economy%20and%20technology-rich%20environment,%20many%20Americans%20are%20spending%20less%20time%20asleep.%20%20The%20Center%20for%20Disease%20Control%20and%20Prevention%20%28CDC%29%20revealed%20that%20more%20than%2035%%20of%20the%2074,571%20adult%20Americans%20surveyed%20get%20less%20than%207%20hours%20of%20sleep%20a%20day%20and%2037.9%%20reported%20%E2%80%9Cunintentionally%20falling%20asleep%20during%20the%20day%20at%20least%20once%20in%20the%20preceding%20month.%20%20Alarmingly,%20nearly%205%%20of%20respondents%20admitted%20to%20nodding%20off%20while%20driving%20at%20least%20once%20in%20the%20past%20month.%204%20%20%20Furthermore,%20it%20is%20estimated%20that%20sleep%20deprivation%20causes%20nearly%20100,000%20vehicle%20crashes%20and%201,500%20deaths%20annually%20in%20the%20U.S.5%20Perhaps,%20if%20people%20more%20strictly%20followed%20the%20CDC%E2%80%99s%20recommendation%20of%20getting%207-9%20hrs%20of%20sleep%20%28for%20adults%29,%20such%20scary%20statistics%20will%20improve%20and%20save%20our%20economy%20billions%20of%20dollars.%20%20But%20why%20does%20the%20CDC%20discuss%20anything%20about%20sleep?%20%20Does%20sleep%20have%20a%20role%20in%20disease%20prevention?%20%20We%20know%20what%20happens%20to%20our%20bodies%20when%20we%20are%20sleep%20deprived:%20red%20eyes,%20achy%20joints,%20and%20sometimes%20we%20even%20catch%20a%20cold.%20%20Besides%20behavioral%20problems%20that%20arise%20when%20we%20are%20sleep%20deprived,%20our%20immune%20system%20becomes%20compromised%20as%20well.%20%20For%20that%20reason,%20the%20CDC%20warns,%20%E2%80%9Cpersons%20experiencing%20sleep%20insufficiency%20are%20also%20more%20likely%20to%20suffer%20from%20chronic%20diseases%20such%20as%20hypertension,%20diabetes,%20depression%20and%20obesity%E2%80%A6%E2%80%9D%20The%20CDC%20refers%20to%20America%E2%80%99s%20sleep%20deprivation%20problem%20as%20an%20epidemic,%20a%20public%20health%20concern.%20%20The%20problem%20of%20sleep%20deprivation%20in%20America%20is%20so%20great%20that%20since%20there%20is%20even%20a%20national%20organization%20called%20the%20National%20Sleep%20Foundation%20devoted%20to%20alerting%20the%20public,%20policy%20makers%20and%20healthcare%20providers%20of%20the%20consequences%20related%20to%20sleeping%20insufficiencies.%20Such%20agencies%20are%20worried%20that%20a%20continuously%20sleepy%20Nation%20will%20result%20in%20a%20sick%20Nation%20with%20increased%20susceptibility%20to%20infections%20and%20disease-which%20ultimately%20will%20cost%20the%20country%20billions%20and%20hamper%20productivity.%20%20%20Sleep%20Deprivation:%20The%20Immunology%20Behind%20It%20First,%20how%20does%20one%20define%20and%20measure%20sleep?%20There%20are%20two%20types%20of%20sleep:%20non-rapid-eye-movement%20%28NREM%29%20and%20rapid%20eye-movement%20%28REM%29.%20%20%20%20There%20are%205%20main%20stages%20of%20sleep%20beginning%20with%20stage%201%20in%20which%20you%20are%20just%20lying%20down%20to%20sleep,%20but%20still%20pretty%20conscious.%20%20Stage%202%20follows%20with%20a%20lower%20level%20of%20consciousness%20that%20develops%20into%20stages%20and%203%20and%204.%20%20Stages%203%20and%204%20are%20collectively%20called%20slow%20wave%20sleep%20%28SWS%29.%20%20Under%20SWS,%20the%20brain%20is%20at%20its%20lowest%20level%20of%20consciousness%20and%20is%20thought%20to%20be%20involved%20in%20restorative%20functions.%20%20Lastly,%20REM%20is%20the%20final%20step%20in%20sleep%20and%20is%20when%20our%20brains%20are%20processing%20information%20and%20dreaming.%20%20When%20asleep,%20we%20typically%20spend%20equal%20parts%20in%20REM%20and%20SWS.%20%20Sleep%20stages%20can%20be%20monitored%20via%20EEG%20recordings%20as%20each%20stage%20has%20distinctly%20different%20frequencies%20and%20EEG%20wave%20amplitudes.6%20In%20the%20late%201980%E2%80%99s%20and%20early%201990%E2%80%99s,%20Toth%20and%20colleagues%20performed%20a%20series%20of%20infections%20on%20rabbits%20and%20monitored%20the%20animal%E2%80%99s%20sleep%20patterns%20during%20infections.%20%20They%20tested%20a%20virus%20%28influenza%29,%20bacteria%20%28Staph.%20aureus%20and%20E.%20coli%20%29,%20yeast%20%28Candida%20albicans%29%20and%20parasite%20%28Trypansosoma%20brucei%29.%20%20Each%20infection%20resulted%20in%20abhorrent%20sleep%20patterns,%20regardless%20of%20microorganism.%20%20In%20general,%20the%20various%20infections%20increased%20the%20duration%20of%20slow%20wave%20sleep%20%28SWS%29.%206,7%20So%20the%20observation%20that%20infection%20increases%20SWS,%20but%20not%20other%20sleep%20stages,%20may%20mean%20that%20SWS,%20in%20particular,%20regulates%20our%20immune%20response%20while%20we%20are%20sleeping.%20%20In%20humans,%20one%20of%20the%20most%20well%20studied%20infections%20to%20examine%20in%20regards%20to%20sleep%20is%20T.%20brucei,%20the%20parasite%20that%20causes%20Human%20African%20trypanosomiasis%20aka%20African%20sleeping%20sickness.%20%20Infected%20individuals,%20usually%20by%20the%20second%20year%20of%20infection,%20lose%20the%20ability%20to%20manage%20their%20circadian%20rhythm%20resulting%20in%20the%20complete%20loss%20of%20sleep%20regulation%20and%20often%20leads%20to%20comatose.%20%20In%20mice%20and%20rabbits,%20the%20release%20of%20parasites%20into%20the%20bloodstream%20is%20associated%20with%20acute%20increases%20in%20SWS,%20however%20this%20has%20not%20been%20evaluated%20in%20humans.%206%20%20So%20what%20immune%20factors%20are%20modulated%20by%20sleep?%20%20First,%20it%20is%20known%20that%20the%20majority%20of%20our%20immune%20cells,%20B%20and%20T%20cells%20and%20monocytes%20reach%20maximal%20levels%20in%20the%20blood%20during%20the%20night%20and%20are%20lowest%20when%20awake.8%20In%20addition,%20the%20pro-inflammatory%20cytokines,%20TNFalpha%20and%20IL-1beta%20plasma%20levels%20also%20peak%20while%20we%20sleep,%20being%20the%20highest%20at%20the%20onset%20of%20SWS.8%20An%20increase%20of%20either%20of%20these%20cytokines%20subsequently%20increases%20SWS%20duration,%20whereas%20decreases%20in%20TNFalpha%20or%20IL-1beta%20blocks%20SWS.6%20This%20appears%20to%20be%20the%20clearest%20example%20of%20how%20our%20sleep%20patterns%20may%20regulate%20our%20immune%20response%20during%20infection.%20Both%20of%20these%20cytokines%20are%20critical%20in%20the%20clearance%20of%20infection%20and%20are%20some%20of%20the%20most%20abundant%20cytokines%20present%20during%20infectious%20diseases.%20%20Therefore%20it%20seems%20to%20make%20sense%20why%20an%20increase%20in%20SWS%20during%20the%20diseases%20mentioned%20above%20occurs.%20%20%20Interestingly,%20infection%20is%20not%20the%20only%20thing%20that%20induces%20TNFa%20and%20IL-1beta%20release%20in%20the%20brain%20and%20plasma.%20%20Sleep%20deprivation%20also%20promotes%20pro-inflammatory%20cytokine%20release,%20which%20then%20instructs%20your%20brain%20to%20increase%20the%20time%20it%20spends%20in%20SWS.%20%20Alternatively,%20anti-inflammatory%20cytokines%20such%20as%20IL-10%20is%20thought%20to%20inhibit%20SWS%20onset%20by%20antagonizing%20IL-1beta%20and%20TNFalpha.%20%20It%20is%20also%20thought%20the%20induction%20of%20certain%20hormones%20such%20growth%20hormone%20%28GH%29%20and%20prolactin%20promote%20the%20release%20of%20IL-1beta,%20since%20inhibiting%20these%20hormones%20attenuates%20IL-1beta%20levels%20and%20SWS%20duration.%20%20Conversely,%20the%20anti-inflammatory%20hormone,%20cortisol%20does%20the%20opposite,%20and%20decreases%20IL-1beta%20production.6%20So%20it%20appears%20that%20our%20immune%20system%20mirrors%20our%20endocrine%20system%20in%20that%20they%20both%20regulate%20our%20sleep%20patterns%20by%20releasing%20pro-%20and%20anti-%20sleep%20mediators.%20%20%20TNFalpha%20and%20IL-1beta%20are%20generally%20thought%20of%20activators%20of%20the%20innate%20immune%20response,%20such%20as%20macrophages%20and%20dendritic%20cells.%20%20Such%20cytokines%20act%20as%20adjuvents,%20preparing%20the%20macrophage%20and%20dendritic%20cell%20to%20be%20potent%20antigen%20presenting%20cells%20%28APC%29.%20%20The%20main%20job%20of%20an%20APC,%20is%20to%20display%20bits%20of%20processed%20pathogen%20%28antigen%29%20to%20a%20T%20cell.%20%20Once%20a%20T%20cell%20recognizes%20a%20particular%20antigen,%20it%20then%20becomes%20activated%20and%20ready%20to%20fight%20the%20infection%20and%20help%20B%20cells%20secrete%20antibodies.%20%20Sleep%20may%20also%20affect%20the%20way%20our%20bodies%20fight%20diseases.%20%20In%20a%20few%20human%20studies,%20it%20was%20revealed%20that%20the%20number%20of%20T%20helper%20cells%20decreased%20and%20the%20level%20circulating%20antibodies%20decreased%20with%20sleep%20deprivation.6%20Not%20surprisingly,%20when%20the%20body%20is%20pushed%20to%20the%20extreme%20of%20total%20sleep%20deprivation,%20the%20immune%20system%20fails%20completely.%20%20In%20one%20study,%20rats%20were%20sleep%20deprived%20for%2021%20days,%20until%20near%20death.%20%20At%20the%20end%20of%20the%2021%20days,%20the%20rats%20had%20suffered%20from%20severe%20weight%20loss%20and%20septicemia%20with%20both%20opportunistic%20and%20pathogenic%20microbes%20in%20the%20blood.9%20Furthermore,%20a%20recent%20survey%20of%20more%20than%20a%20million%20participants%20demonstrated%20a%20correlation%20between%20sleep%20of%20less%20than%207%20hours%20a%20night%20and%20increased%20mortality.10%20%20%20Sleep%20Deprivation%20and%20Disease:%20Why%20This%20Research%20Paper%20Matters%20The%20evidence%20seems%20pretty%20clear:%20our%20immune%20system%20communicates%20with%20our%20brain%20while%20we%20sleep,%20but%20researchers%20have%20only%20begun%20scratching%20at%20the%20mechanisms%20behind%20this%20phenomenon.%20%20This%20is%20very%20exciting%20and%20novel%20research%20that%20may%20provide%20not%20only%20insight%20into%20how%20the%20body%20operates,%20but%20also%20instigate%20new%20therapeutic%20approaches%20in%20fighting%20disease.%20%20Although%20it%20is%20well%20established%20the%20role%20of%20certain%20cytokines%20in%20maintaining%20healthy%20sleep%20cycles%20and%20how%20the%20immune%20system%20responds%20to%20sleep%20deprivation,%20little%20is%20known%20about%20the%20effect%20sleep%20has%20on%20specific%20immune%20cell%20function.%20%20The%20majority%20of%20what%20we%20know%20about%20the%20interplay%20between%20sleep%20and%20immune%20function%20is%20correlative.%20%20For%20example,%20we%20know%20TNFalpha%20can%20promote%20APC%20function,%20and%20we%20know%20that%20TNFalpha%20levels%20increase%20during%20SWS,%20but%20it%20remains%20elusive%20whether%20sleep-induced%20TNFalpha%20promote%20APC%20function%20and%20thereby%20program%20and%20effective%20T%20cell%20response.%20%20Sleep%20may%20represent%20a%20crucial%20part%20of%20the%20immune%20system%20that%20has%20been%20largely%20ignored%20by%20the%20immunological%20and%20medical%20fields.%20%20Perhaps,%20the%20notion%20%E2%80%9CSick%20and%20Tired%E2%80%9D%20can%20be%20immunologically%20explained%20and%20that%20greater%20insight%20into%20how%20sleep%20affects%20the%20body%E2%80%99s%20ability%20to%20clear%20infection%20is%20an%20underlying%20mechanism%20behind%20the%20increase%20of%20infections%20among%20infants%20and%20the%20elderly%20%28acute%20vs%20chronic%20sleep%20deprivation%29.%20%20How%20does%20sleep%20impact%20our%20ability%20to%20properly%20activate%20our%20immune%20system?%20%20Can%20sleep%20play%20a%20role%20in%20designing%20better%20therapies%20and%20treatments%20for%20people%20fighting%20disease?%20%20%20These%20questions%20motivate%20Jan%20Born%E2%80%99s%20research%20group%20at%20the%20University%20of%20Lubeck%20in%20Germany%20to%20find%20new%20ways%20to%20make%20more%20efficient%20vaccines%E2%80%A6without%20changing%20the%20vaccine%20components.%20%20Therefore,%20as%20Lange,%20T.%20et%20al%20illustrates%20in%20their%20recent%20Journal%20of%20Immunology%20paper,%20a%20little%20sleep%20can%20make%20all%20the%20difference%20in%20getting%20the%20most%20out%20of%20your%20next%20vaccination.%20%20What%20the%20&*%$#%21%20Does%20the%20Title%20Mean?%21%20Lange,%20T.%20et%20al.%20%E2%80%9CSleep%20after%20vaccination%20boosts%20immunological%20memory%E2%80%9D.%20Journal%20of%20Immunology.%20187%20%282011%29.%20%201%29The%20essential%20point%20of%20vaccination%20is%20providing%20people%20with%20the%20antibodies%20needed%20to%20clear%20infections%20quickly%20and%20effectively.%20%20Vaccines%20work%20by%20administering%20something%20that%20stimulates%20the%20adaptive%20immune%20response%20without%20causing%20disease.%20%20Vaccines%20in%20the%20U.S.%20consist%20of%20purified%20proteins%20from%20a%20pathogen%20that%20is%20injected%20or%20inhaled.%20%20When%20APCs%20encounter%20the%20proteins%20in%20the%20vaccine,%20the%20APCs%20will%20process%20them%20into%20that%20will%20then%20short%20peptide%20sequences.%20%20Once%20processed,%20an%20APC%20presents%20the%20peptide%20on%20its%20surface%20to%20a%20T%20helper%20cell.%20%20At%20the%20moment%20when%20the%20T%20helper%20cell%20recognizes%20a%20certain%20peptide%20sequence,%20the%20T%20cell%20begins%20to%20proliferate%20and%20secrete%20cytokines%20that%20help%20B%20cells%20secrete%20tons%20of%20antibodies-%20all%20of%20which%20can%20specifically%20target%20the%20protein%20that%20was%20used%20in%20the%20vaccine.%20%20Vaccines%20help%20prevent%20infectious%20diseases%20by%20assisting%20our%20immune%20system%20in%20making%20the%20antibodies%20necessary%20to%20clearing%20an%20infection%20quickly.%20%20When%20we%20become%20infected%20with%20something%20that%20we%20didn%E2%80%99t%20vaccinate%20against,%20our%20immune%20system%20has%20to%20take%20a%20lot%20of%20time%20%28weeks%29%20to%20produce%20the%20antibodies%20needed%20to%20fight%20the%20infection.%20%20Some%20pathogens%20are%20extremely%20virulent%20and%20can%20cause%20a%20lot%20of%20harm,%20even%20death%20in%20the%20weeks%20it%20takes%20our%20bodies%20to%20properly%20protect%20itself%20against%20it.%20%20Vaccines%20therefore%20help%20equip%20our%20immune%20system%20with%20the%20weapons%20%28antibodies%29%20it%20needs,%20before%20even%20heading%20into%20battle%20against%20a%20deadly%20pathogen.%20%202%29Of%20course,%20this%20concept%20of%20a%20vaccine%20works%20best%20when%20the%20immune%20system%20can%20remember%20what%20the%20pathogen%20looks%20like%20when%20it%20encounters%20it%20a%20month,%20a%20year,%20or%2010%20years%20from%20the%20time%20of%20vaccination.%20%20This%20is%20immunological%20memory.%20%20An%20amazing%20aspect%20of%20your%20immune%20system%20is%20that%20when%20the%20adaptive%20immune%20cells,%20B%20and%20T%20cells,%20are%20activated%20and%20proliferate,%20some%20of%20the%20cells%20seem%20to%20last%20forever.%20%20These%20cells%20are%20aptly%20named,%20memory%20B%20and%20T%20cells.%20%20These%20memory%20cells%20will%20last%20you%20during%20your%20entire%20life%20time,%20always%20remembering%20what%20they%20are%20supposed%20to%20do%20when%20they%20encounter%20the%20specific%20protein%20or%20peptide%20that%20stimulated%20them%20to%20become%20active%20in%20the%20first%20place.%20%20In%20order%20to%20maximize%20immunogenicity%20and%20achieve%20immunological%20memory%20you%20need%20a%20very%20good%20induction%20of%20the%20antigen-presenting%20cells%20by%20using%20adjuvants%20and%20booster%20shots%20to%20bolster%20the%20ability%20of%20your%20body%20to%20produce%20a%20reservoir%20of%20effective%20memory%20cells%20ready%20to%20kill%20a%20particular%20pathogen%20over%20the%20course%20of%20your%20life%21%20%20%20Compile%20this%20information%20together%20and%20we%20can%20infer%20that:%20Sleep%20may%20act%20as%20an%20adjuvant%20to%20a%20vaccine%20enabling%20the%20development%20of%20memory%20B%20and%20T%20cells%20that%20provides%20immunological%20protection%20against%20a%20certain%20pathogen%20for%20years.%20%20Ready%20for%20an%20adventure?%20Read%20on%20for%20a%20guided-tour%20through%20the%20scientific%20data%21%20%20%20%20%20%20%20References%20and%20Further%20Reading:%201.%09Hosford,%20M.%20et%20al.%20%E2%80%9CAir%20traffic%20controller%20asleep%20on%20duty%20at%20Reagan%20National,%20NTSB%20says%E2%80%9D.%20ABC%20News.%20%282011%29.%202.%09Beers,%20TM.%20%E2%80%9CFlexible%20schedules%20and%20shift%20work:%20replacing%20the%20%E2%80%9C9-to-5%E2%80%9D%20workday?%E2%80%9D.%20Monthly%20Labor%20Review.%20%282000%29.%203.%09Awake%20in%20Philly%20Community%20Education%20Group.%20%E2%80%9CFact%20sheet:%20shift%20work%20sleep%20disorder%E2%80%9D.%20%282004%29.%204.%09CDC.%20%E2%80%9CInsufficient%20sleep%20is%20a%20public%20health%20epidemic%E2%80%9D.%20%282011%29.%205.%09US%20Department%20of%20Transportation,%20National%20Highway%20Traffic%20Safety%20Administration,%20National%20Center%20on%20Sleep%20Disorders%20Research,%20National%20Heart%20Lung%20and%20Blood%20Institute.%20%E2%80%9CDrowsy%20driving%20and%20automobile%20crashes%E2%80%9D%20%282011%29.%206.%09Bryant,%20PA.,%20et%20al.%20%E2%80%9CSick%20and%20tired:%20does%20sleep%20have%20a%20vital%20role%20in%20the%20immune%20system?%E2%80%9D%20Nature%20Reviews%20Immunology.%204:457-467.%20%282004%29.%207.%09Toth,%20LA.,%20et%20al.%20%E2%80%9CAlteration%20of%20sleep%20in%20rabbits%20by%20Staphylococcus%20aureus%20infection%E2%80%9D.%20Infect.%20Immunity.%2058:%201785-1791.%20%281988%29.%208.%09Born,%20J.,%20et%20al.%20%E2%80%9CEffects%20of%20sleep%20and%20circadian%20rhythm%20on%20human%20circulating%20immune%20cells%E2%80%9D.%20Journal%20of%20Immunology.%20158:4454-4464.%20%281997%29.%209.%09Everson,%20CA.%20%E2%80%9CSustained%20sleep%20deprivation%20impairs%20host%20defense%E2%80%9D.%20Am.%20J.%20Physiol.%20265:R1148-R1154.%20%281993%29.%2010.%09Kripke,%20DF.,%20et%20al.%20%E2%80%9CMortality%20associated%20with%20sleep%20duration%20and%20insomnia%E2%80%9D.%20Arch.%20Gen.%20Psychiatry.%E2%80%9D%2059:131-136.%20%282002%29." style="color: magenta;">an air traffic controller at Ronald Reagan Washington Airport fell asleep on the job, leaving two planes alone in the sky trying to land the planes alone.</a><sup>1</sup> Fortunately, in this case, no one was terrible injured, but the news magnified the public’s awareness and outrage of having to depend on sleep-deprived individuals for our safety. It’s not surprising the single air traffic controller fell asleep on the job since it was reported this was “his fourth consecutive overnight shift, which runs from 10 p.m. to 6 a.m.” <sup>1</sup> In fact, the American Academy of Sleep Medicine International Classification of Sleep Disorders classifies this condition as Shift Work Sleep Disorder (SWSD). SWSD plagues nearly 70% of the 15 million Americans who work shifts between 10 p.m. and 6 a.m.<sup>2 </sup> It is further estimated that sleep deprived workers cost U.S. businesses $18 billion a year.<sup>3</sup> </span></div>
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<tr><td style="text-align: center;"><span style="font-size: small;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgTlh08JOk0hQnkgqq7GTt-4_UAFbOcprqgyrGjqicMtTuHvaTl8SUIzhGfB22ZVKtpImYYtZ0H6SUJtm8-uD3rCkwTzOHnWeenYJdeXuhopCw4Vj0dA6eFUxbgtohFzZzz6mIRiwxbcA0/s1600/dsSleep_270px.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgTlh08JOk0hQnkgqq7GTt-4_UAFbOcprqgyrGjqicMtTuHvaTl8SUIzhGfB22ZVKtpImYYtZ0H6SUJtm8-uD3rCkwTzOHnWeenYJdeXuhopCw4Vj0dA6eFUxbgtohFzZzz6mIRiwxbcA0/s400/dsSleep_270px.jpg" width="365" /></a></span></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">from <a href="http://cdc.gov/"><span class="Apple-style-span" style="color: magenta;">cdc.gov</span></a></span></td></tr>
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<span style="font-size: small;">Importantly, sleepiness does not only affect the people who work the “graveyard shift”, but in an increasingly fast-paced society, coupled with a tough economy and technology-rich environment, many Americans are spending less time asleep. The Center for Disease Control and Prevention (CDC) revealed that more than 35% of the 74,571 adult Americans surveyed get less than 7 hours of sleep a day and 37.9% reported “unintentionally falling asleep during the day at least once in the preceding month. Alarmingly, nearly 5% of respondents admitted to nodding off while driving at least once in the past month.<sup> 4</sup> Furthermore, it is estimated that sleep deprivation causes nearly 100,000 vehicle crashes and 1,500 deaths annually in the U.S.<sup>5</sup> Perhaps, if people more strictly followed the CDC’s recommendation of getting 7-9 hrs of sleep (for adults), such scary statistics will improve and save our economy billions of dollars. But why does the CDC discuss anything about sleep? Does sleep have a role in disease prevention? </span></div>
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<span style="font-size: small;">We know what happens to our bodies when we are sleep deprived: red eyes, achy joints, and sometimes we even catch a cold. Besides behavioral problems that arise when we are sleep deprived, our immune system becomes compromised as well. For that reason, the CDC warns, “persons experiencing sleep insufficiency are also more likely to suffer from chronic diseases such as hypertension, diabetes, depression and obesity…”<span style="color: magenta;"> </span><a href="http://www.cdc.gov/Features/dsSleep/" style="color: magenta;">The CDC refers to America’s sleep deprivation problem as an epidemic, a public health concern</a><span style="color: magenta;">.</span> The problem of sleep deprivation in America is so great that since there is even a national organization called the<a href="http://www.blogger.com/goog_2042329289"> <span style="color: magenta;">National Sleep Foundation</span></a><a href="http://www.sleepfoundation.org/primary-links/how-sleep-works" style="color: magenta;"> </a>devoted to alerting the public, policy makers and healthcare providers of the consequences related to sleeping insufficiencies.<sup> </sup>Such agencies are worried that a continuously sleepy nation will result in a sick nation with increased susceptibility to infections and disease-which ultimately will cost the country billions and hamper productivity. </span></div>
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<u><span style="font-size: small;"><i><b>Sleep Deprivation: The Immunology Behind It</b></i></span> </u><br />
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<tr><td class="tr-caption" style="text-align: center;">EEG charts and amount of time spent in each sleep cycle, stages 3 and 4 constitue SWS which is also the time in sleep when pro-inflammatory cytokines, IL-1 and TNFalpha peak. <b>Lange, et al. establishes that a full-night's sleep post vaccination BOOSTS your immunological memory, perhaps enhancing the vaccine's effectiveness. </b><span class="Apple-style-span" style="font-size: xx-small;">Image from <a href="http://seamist.hubpages.com/"><span class="Apple-style-span" style="color: magenta;">seamist.hubpages.com</span></a></span></td></tr>
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<span style="font-size: small;">First, how does one define and measure sleep? There are two types of sleep: non-rapid-eye-movement (NREM) and rapid eye-movement (REM). There are 5 main stages of sleep beginning with stage 1 in which you are just lying down to sleep, but still pretty conscious. Stage 2 follows with a lower level of consciousness that develops into stages and 3 and 4. Stages 3 and 4 are collectively called <b><u>slow wave sleep (SWS).</u></b> Under SWS, the brain is at its lowest level of consciousness and is thought to be involved in restorative functions. Lastly, REM is the final step in sleep and is when our brains are processing information and dreaming. When asleep, we typically spend equal parts in REM and SWS. Sleep stages can be monitored via EEG recordings as each stage has distinctly different frequencies and EEG wave amplitudes.<sup>6</sup></span><br />
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<span style="font-size: small;"><sup> </sup>In the late 1980’s and early 1990’s, Toth and colleagues performed a series of infections on rabbits and monitored the animal’s sleep patterns during infections. They tested a virus (influenza), bacteria (<i>Staph. aureus</i> and <i>E. coli</i> ), yeast (<i>Candida albicans</i>) and parasite (<i>Trypansosoma brucei</i>). Each infection resulted in abhorrent sleep patterns, regardless of microorganism. In general, the various infections increased the duration of slow wave sleep (SWS). <sup>6,7</sup> <b><u>The observation that infection increases SWS, but not other sleep stages, may mean that SWS, in particular, regulates our immune response while we are sleeping.</u></b> In humans, one of the most well studied infections to examine in regards to sleep is <i>T. brucei,</i> the parasite that causes <a href="http://www.who.int/trypanosomiasis_african/en/" style="color: magenta;">Human African trypanosomiasis</a> aka African sleeping sickness. Infected individuals, usually by the second year of infection, lose the ability to manage their circadian rhythm resulting in the complete loss of sleep regulation and often leads to comatose. In mice and rabbits, the release of parasites into the bloodstream is associated with acute increases in SWS, however this has not been evaluated in humans. <sup>6</sup> </span></div>
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<span style="font-size: small;">So what immune factors are modulated by sleep? First, it is known that the majority of our immune cells, B and T cells and monocytes reach maximal levels in the blood during the night and are lowest when awake.<sup>8</sup> In addition, the <b><u style="background-color: magenta;">pro-inflammatory </u><u><span style="background-color: magenta;">cytokines</span>, TNFalpha and IL-1beta plasma levels also peak while we sleep, being the highest at the onset of SWS</u></b>.<sup>8</sup> An increase of either of these cytokines subsequently increases SWS duration, whereas decreases in TNFalpha or IL-1beta blocks SWS.<sup>6</sup> This appears to be the clearest example of how our sleep patterns may regulate our immune response during infection. Both of these cytokines are critical in the clearance of infection and are some of the most abundant cytokines present during infectious diseases. Therefore it seems to make sense why an increase in SWS during the diseases mentioned above occurs. </span></div>
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<span style="font-size: small;">Interestingly, infection is not the only thing that induces TNFa and IL-1beta release in the brain and plasma. Sleep deprivation also promotes pro-inflammatory cytokine release, which then instructs your brain to increase the time it spends in SWS. Alternatively, anti-inflammatory cytokines such as IL-10 is thought to inhibit SWS onset by antagonizing IL-1beta and TNFalpha. It is also thought the induction of certain hormones such growth hormone (GH) and prolactin promote the release of IL-1beta, since inhibiting these hormones attenuates IL-1beta levels and SWS duration. Conversely, the anti-inflammatory hormone, cortisol does the opposite, and decreases IL-1beta production.<sup>6 </sup>So it appears that <b><u>our immune system mirrors our endocrine system in that they both regulate our sleep patterns by releasing pro- and anti- sleep mediators. </u></b></span><br />
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<span style="font-size: small;">TNFalpha and IL-1beta are generally thought of activators of the innate immune response, such as macrophages and dendritic cells. Such cytokines act as an <b style="background-color: magenta;"><u>adjuvent</u></b>, boosting the macrophage and dendritic cell's ability to be potent <b style="background-color: magenta;"><u>antigen presenting cells (APC).</u></b> The main job of an APC, is to display bits of processed pathogen (antigen) to a T cell. Once a T cell recognizes a particular antigen, it then becomes activated and ready to fight the infection and help B cells secrete antibodies. <u><b>Realize that the next time you become ill and start to feel sleepy, your immune system is starting to work and that you should rest so that your body can adequately defend itself against infection. </b></u> Ignoring our body's demand for sleep affects the way our bodies fight diseases. In a few human studies, it was revealed that the number of <span style="background-color: white;">T helper cells </span>decreased and the level circulating antibodies decreased with sleep deprivation.<sup>6</sup> Not surprisingly, when the body is pushed to the extreme of total sleep deprivation, the immune system fails completely. In one study, rats were sleep deprived for 21 days, until near death. At the end of the 21 days, the rats had suffered from severe weight loss and septicemia with both opportunistic and pathogenic microbes in the blood.<sup>9</sup> Furthermore, a recent survey of more than a million participants demonstrated a <a href="http://archpsyc.ama-assn.org/cgi/content/full/59/2/131" style="color: magenta;">strong correlation between sleep of less than 7 hours a night and increased mortality</a>.<sup>10 </sup></span></div>
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<span style="font-size: small;"> <i><b> </b></i></span></div>
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<span style="font-size: small;"><i><b><u>Sleep Deprivation and Disease: Why This Research Paper Matters</u></b></i></span></div>
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<span style="font-size: small;">The evidence is clear: our immune system communicates with our brain while we sleep, but researchers have only begun scratching at the mechanisms behind this phenomenon. This is very exciting and novel research that may provide not only insight into how the body operates, but also instigate new therapeutic approaches in fighting disease. Although it is well established the role of certain cytokines in maintaining healthy sleep cycles and how the immune system responds to sleep deprivation, little is known about the effect sleep has on specific immune cell function. The majority of what we know about the interplay between sleep and immune function is correlative. For example, we know TNFalpha can promote APC function, and we know that TNFalpha levels increase during SWS, but it remains elusive whether sleep-induced TNFalpha promote APC function and thereby program and effective T cell response. Sleep may represent a crucial part of the immune system that has been largely ignored by the immunological and medical fields. Perhaps, the notion “Sick and Tired” can be immunologically explained and that greater insight into how sleep affects the body’s ability to clear infection is an underlying mechanism behind the increase of infections among infants and the elderly (acute vs chronic sleep deprivation). How does sleep impact our ability to properly activate our immune system? Can sleep play a role in designing better therapies and treatments for people fighting disease? These questions motivate Jan Born’s research group at the University of Lubeck in Germany to find new ways to make more efficient vaccines…without even changing the vaccine components! <b><span style="color: magenta;">Therefore, as Lange, T. et al illustrates in their recent </span><i style="color: magenta;">Journal of Immunology</i><span style="color: magenta;"> paper, catching a full night of ZZZ's can make all the difference in getting the most out of your next vaccination.</span></b></span></div>
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<u><span style="font-size: small;"><i><b>What the &*%$#! Does the Title Mean?!</b></i></span> </u></div>
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<span style="font-size: small;">Lange, T. et al. <a href="http://www.jimmunol.org/content/early/2011/05/29/jimmunol.1100015.abstract"><b><span style="color: magenta;">“Sleep after vaccination boosts immunological memory”. </span><i><span class="Apple-style-span" style="color: magenta;">Journal of Immunology</span></i><span style="color: magenta;">. 187 (2011).</span></b></a></span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-size: x-small;">There are two waves of antibody response: a slower, short-lived response during the initial infection followed by a quicker, longer-lived memory response . </span><span style="font-size: xx-small;">from<span class="Apple-style-span" style="color: magenta;"> <a href="http://click4biology.info/"><span class="Apple-style-span" style="color: magenta;">click4biology.info</span></a></span></span></td></tr>
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<span style="font-size: small;">1) The essential point of <b style="background-color: magenta;"><u>vaccination</u></b> is providing people with the antibodies needed to clear infections quickly and effectively. Vaccines work by administering something that stimulates the adaptive immune response without causing disease. Vaccines in the U.S. consist of purified proteins (not a whole, intact pathogen) from a pathogen that is injected or inhaled. When APCs encounter the proteins in the vaccine, they cut the proteins into short peptide sequences. Once processed, an APC presents the peptide on its surface to a <u style="background-color: magenta;"><b>T helper cell</b></u>, which are named so because they help B cells make antibodies and help innate immune cells to destroy pathogens. At the moment when the T helper cell recognizes a certain peptide sequence, the T cell begins to proliferate and secrete cytokines that help B cells secrete tons of <u style="background-color: magenta;"><b>antibodies</b></u>- all of which can specifically target the protein that was used in the vaccine. Vaccines help prevent infectious diseases by assisting our immune system in making the antibodies necessary to clearing an infection quickly. When we become infected with something that we didn’t vaccinate against, our immune system has to take a lot of time (weeks) to produce the antibodies needed to fight the infection. Some pathogens are extremely virulent and can cause a lot of harm, even death in the weeks it takes our bodies to properly protect itself against it. Vaccines therefore help equip our immune system with the weapons (antibodies) it needs, before even heading into battle against a deadly pathogen. </span><br />
<span style="font-size: small;"> 2) Of course, this concept of a vaccine works best when the immune system can remember what the pathogen looks like when it encounters it a month, a year, or 10 years from the time of vaccination. This is <b style="background-color: magenta;"><u>immunological memory</u></b>. An amazing aspect of your immune system is that when the adaptive immune cells, B and T cells, are activated and proliferate, some of the cells seem to last forever. These cells are aptly named, memory B and T cells. These memory cells will last you during your entire life time, always remembering what they are supposed to do when they encounter the specific protein or peptide that stimulated them to become active in the first place. In order to maximize immunogenicity and achieve immunological memory you need a very good induction of the antigen-presenting cells by using adjuvants and booster shots to bolster the ability of your body to produce a reservoir of effective memory cells ready to kill a particular pathogen over the course of your life!</span></div>
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<span style="font-size: small;">Compile this information together and we can infer that: <span id="goog_1313317569"></span><b style="color: magenta;">Sleep following a vaccination, acts like an adjuvent promoting the development of memory cells that provides long-term immunological protection against a certain pathogen. <u><span id="goog_1313317570"></span></u></b><i><b> </b></i></span></div>
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<span style="font-size: small;"><i><b><u>Ready for an adventure? Read on for a guided-tour through the scientific data!</u></b></i></span></div>
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<span style="font-size: small;">But first: A brief Q and A session regarding the overall experimental approach:</span></div>
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<u><b><span style="font-size: small;">Q) What organism(s) was being tested?</span></b></u></div>
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<span style="font-size: small;">A) All of the experiments presented here were performed on human volunteers. The sample size consisted of 27 healthy, nonsmoking men with an average age of 26. The group was on synchronized schedules with the same sleep-wake patterns for the 6 weeks prior to experimental testing. All sleep-wake activity occurred in a sleep laboratory, and all participants had spent at least one night in the lab prior to experimental testing. The group was randomly assigned to either the “sleep” or “wakefulness” group. </span></div>
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<u><b><span style="font-size: small;">Q) How did the “sleep” group differ from the “wakefulness” group?</span></b></u></div>
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<span style="font-size: small;">A) The sleep patterns between the groups only differ the night following their vaccination (which occurred at 8am and occurred 3 times, one in Feb., March, and June. The “sleep” group had lights off at 11pm and lights on at 6:30am in the sleep laboratory. During this same time, the “wakefulness” group stayed awake in bed watching TV, reading, listening to music or talking to a scientist (fun, no?) The “wake” group was not allowed to sleep until 8pm the following day. This may seem a bit extreme and rare that people would be awake for this long following a vaccine shot, but it does adequately distinguish the two experimental groups clearly. </span></div>
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<u><b><span style="font-size: small;">Q) What vaccine was used?</span></b></u></div>
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<span style="font-size: small;">A) Hepatitis A vaccine (Twinrix, GlaxoSmithKline Biologicals)</span></div>
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<u><b><span style="font-size: small;">Q) What did the researchers monitor throughout the trial period?</span></b></u></div>
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<span style="font-size: small;">A) Four major conditions were tested:</span></div>
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<span style="font-size: small;">1. Sleep activity via electroencephalography (EEG) to examine sleep stages.</span></div>
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<span style="font-size: small;">2. Hormone analysis to investigate sleep-related hormone release via i.v. blood collection.</span></div>
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<span style="font-size: small;">3. Hepatitis A Virus (HAV) - specific T helper cell response</span></div>
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<span style="font-size: small;">4. HAV - specific antibody response</span></div>
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<span style="font-size: small;">For immune response, peripheral blood cells (to look at T cells) and serum (where antibodies are found) was collected by drawing blood immediately before vaccination and then 1,2, and 4 weeks after each shot as well as a follow-up at 1 yr. after the first inoculation.</span></div>
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<i><b><span style="font-size: small;"><u>Now let’s dive into the results!</u></span></b></i></div>
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<span style="font-size: small;">Because the whole basis of this paper rests on sleep activity it is first imperative that the authors of the paper show that the people in the “sleep” group slept normally. Normal meaning that they spent time in each of the known sleep stages (see the above figure) that fit data that is already well established in the field, with nearly 50% of sleep spent in slow wave sleep (SWS; stages 3+4) and 50% in REM sleep. There was no significant differences between the three sleep nights post vaccination. </span></div>
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<span style="font-size: small;">Over the course of the Hepatitis A vaccination period, blood was obtained to examine the T cell response. This is very important to look at because it is a standard read-out for the quality of a vaccine. Recall that most vaccines, including the Hepatitis A vaccine, consist of purified proteins that contain immunogenic Hepatitis A viral proteins. Once these proteins are injected, they enter the blood and tissue where they will be taken up by macrophages and dendritic cells. Which is very convenient since these cells are antigen-presenting cells (APCs). So then these APCs digest the viral proteins into smaller peptides and present these peptides on their surface so T cells can “see” the peptide. If a T cell recognizes that particular peptide, the T cells become divides rapidly producing hundreds of more T cells that all are specific for that peptide. <u><b>Scientists can find out how well a vaccine is working by determining how many vaccine-specific T cells there are-the more there are, the more protection will be provided, the better the vaccine.</b></u><u><b> </b></u> When a T helper cell encounters a peptide it’s specific for, it not only divides like crazy but it also upregulates an activation marker on its surface called CD40L. For the purpose of this paper, it’s just important to understand that some proteins like CD40L can be used as a diagnostic tool to track the progression of T cell activation following vaccination. In this experiment, Lange and colleagues, drew blood from the HAV-vaccinated men in both the “sleep” and “wakefulness” groups, then stimulated the blood cells with a pool of HAV peptides for 6 hours. In this short amount of time, the only cells expressing CD40L are T helper cells that responded to and are therefore specific for HAV. In both groups, the % of CD40L+ HAV-specific T helper cells increases. It is important to note, that quickly following a shot, there is increase followed by a plateau of activated HAV-specific T helper cells and that with each vaccine shot, the T cell response to the vaccine increases; this is the purpose of booster shots. <b><span style="color: magenta;">The surprising result was that by the second HAV shot, there was a significantly lower T helper response in the “wakefulness” group than the “sleep” group. <u> Intriguingly, this difference lasted even 1 year after the initial vaccine shot with the “sleep” group having 2 times the number of activated, HAV-specific T helper cells than the “wakefulness” group. </u> Remember that the only major variable between the groups is that the “sleep” group went to sleep the night following the vaccination shots and the “wakefulness” group did not. This one difference in sleep scheduling contributed to a two-fold difference in T cell activation and response to the HAV vaccine!</span></b></span></div>
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<span style="font-size: small;"><b><span style="color: magenta;"> </span></b>Remember that T helper cells are called “helpers” because they produce <u style="background-color: magenta;"><b>cytokines</b></u> that help other immune cells to become activated and better responsive to the vaccine leading to better protection against pathogens. To make sure that the HAV-specific T helper cells they were detecting were in fact “helpers”, Lange, et al. measured various cytokines produced from CD40L+ cells in response to the HAV peptide pool. <b><span style="color: magenta;">In all the cytokines tested, the “sleep” group produced significantly more cytokines (Interferon(IFN)gamma, Interleukin(IL)-2, Tumor necrosis factor(TNF)alpha, and IL-4) than the group didn’t go to sleep after getting their vaccine shot. </span></b></span></div>
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<span style="font-size: small;"> In addition, T helper cells are “helpers” because they “help” B cells to produce and release antibodies (IL-4 helps this, for example). Because antibodies are one of the major ways vaccines work to protect you against pathogens, the authors of this paper needed to assess whether antibody production is also affected by sleep. To do this, they need to isolate the serum from the blood cells when they collect the blood samples. Once they have the serum, which contains proteins and antibodies but not cells, they can look for HAV-specific antibodies-which is basically like searching for a needle in a haystack. However, researchers can find HAV-specific antibodies in serum by performing an <a href="http://en.wikipedia.org/wiki/ELISA"><u style="color: magenta;"><b>Enzyme-LinkedImmunosorbent Assay (ELISA)</b></u></a>. The basis for an ELISA is using a culture plate coated with HAV proteins and then adding serum to the coated plate. After a brief incubation period, the plate is washed thoroughly, and because antibodies bind extremely well to specific proteins, only the HAV-specific antibodies will stick to the plate, whereas the non-HAV antibodies floating in the serum will be washed away. Finally, the amount of HAV-specific antibodies present (antibody titer) can be determined easily. By this method, which is a very common, standard method used by immunologists and medical professionals, <b style="color: magenta;">they found the people who slept the night following a vaccine shot produced significantly more HAV-specific IgG antibodies compared to those who didn’t get any sleep!</b></span></div>
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<span style="font-size: small;">What is very interesting is that the percentage of HAV-specific T helper cells greatly correlated with the sleep stage #4 compared to the other sleep stages, suggesting that something was present during sleep stage #4 might be regulating this phenomena. Lange, et al. had found that hormones such as growth hormone (GH) and prolactin levels increased profoundly during SWS period. <u><b>Recall, that these hormones induce an inflammatory response, which has been studied extensively as a way the body regulates itself to become sleepy. What is less known, is if these sleep-associated hormones have a role during the immune response as well.</b></u><u><b> </b></u> <b style="color: magenta;">What <i>these</i> data indicate is that GH and prolactin not only regulates the brain to induce sleep, but they also regulate the immune system to induce a highly activated immune response upon vaccination!</b><b style="color: magenta;"> </b> </span></div>
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<span style="font-size: small;"> Furthermore, during SWS, cortisol levels –which is immunosuppressive- is very low. Given these data, the authors hypothesized that increase in GH and prolactin coupled with the decrease in cortisol levels during SWS provided a boost to the HAV vaccine that the “wakefulness” group did not receive. In this way, these sleep-associated hormones behave like an adjuvant that further stimulates APCs to activate T helper cells. By determining an “adjuvant factor” (GH x prolactin divided by cortisol levels), and correlating this “adjuvant factor” with the percent of HAV-specific T helper cells, <b style="color: magenta;">Lange, et al. discovered the production of GH, prolactin and cortisol can eloquently predict the development of a strong HAV-specific immune response!</b></span></div>
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<span style="font-size: small;">As the authors admit, “the immunoregulatory functions of sleep are not well understood”. Which makes this particular research so exciting and novel! Of course, there are lots to expand upon and investigate to better understand how exactly these sleep-associated hormones boost the immune response to the HAV vaccine. It would also be very interesting to know if sleep affects other vaccines besides HAV and if sleep cycles in women or people who are older or younger than the group tested in this paper provide similar results. From an immunologist’s perspective, I think it would be valuable to know not only if the development of immune response to the HAV vaccine is significantly better, but also if the immune response is functionally improved because of sleep. Which will be difficult to do in humans (people are ok with volunteering for a HAV vaccine, but to also volunteer to get infected with HAV? Probably not so great.) But perhaps this aspect could be assessed in mice or by looking at sleep patterns among people who have Hepatitis A and seeing if there is a smaller viral titer in people who sleep more. It might seem ridiculous, that this paper rests all of its results on the one difference of either sleeping 7.5 hours or not sleeping at all, because it might appear that this data is only applicable if you are an insomniac. </span><span style="font-size: small;">It would be interesting to know what exactly the threshold of sleep (hours) is required to see the phenomena they illustrate in this paper. </span><span style="font-size: small;">However, <b style="color: magenta;"><u>what this research provides is strong evidence that little to no sleep has a profound effect on the development of your immune response during vaccination.</u> Interestingly, </b></span><b style="color: magenta;"><span style="font-size: small;">it would be important to test if sleep-associated hormones have a similar effect during infection with a live virus since </span><span style="font-size: small;">this data might provide new insight into why newborns are highly susceptible to such infections (what newborn do you know that sleeps 7+ hours a night?) and why people who work 16+ hour days or graveyard shifts spend more time sick than people who work 9-5. </span></b></div>
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<span style="font-size: small;">Since starting graduate school, I’ve noticed that I have spent more days a year sick than I ever have, I used to think it was because of my increase use of public transportation, living in a bigger city, and interacting with more people (big lab, friends, students of mine, seminars, etc) than I had in my past. But now, I think that I had been neglecting one of the major differences between life before graduate school and now: longer hours working in the lab generally means less sleep at home. As if I needed another motivational reason to be done with graduate school!</span></div>
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<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_white.png" style="border: 0;" /></a></span>
<span class="Z3988" style="font-size: x-small;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+immunology+%28Baltimore%2C+Md.+%3A+1950%29&rft_id=info%3Apmid%2F21632713&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Sleep+after+vaccination+boosts+immunological+memory.&rft.issn=0022-1767&rft.date=2011&rft.volume=187&rft.issue=1&rft.spage=283&rft.epage=90&rft.artnum=&rft.au=Lange+T&rft.au=Dimitrov+S&rft.au=Bollinger+T&rft.au=Diekelmann+S&rft.au=Born+J&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Clinical+Research%2C+Physiology%2C+Genetics%2C+Neuroscience%2C+Sleep%2C+Metabolism%2C+Vaccines">Lange T, Dimitrov S, Bollinger T, Diekelmann S, & Born J (2011). Sleep after vaccination boosts immunological memory. <span style="font-style: italic;">Journal of immunology (Baltimore, Md. : 1950), 187</span> (1), 283-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21632713" rev="review"><span class="Apple-style-span" style="color: magenta;">21632713</span></a></span><br />
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<b><u><i><span style="font-size: x-small;">References and Further Reading:</span></i><span style="font-size: x-small;"> </span></u></b></div>
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<span style="font-size: x-small;">1.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Hosford, M. et al. <a href="http://abcnews.go.com/Travel/air-traffic-controller-staffing-reviewed-planes-land-dc/story?id=13210625"><span class="Apple-style-span" style="color: magenta;">“Air traffic controller asleep on duty at Reagan National, NTSB says”</span></a>. ABC News. (2011). </span><br />
<span style="font-size: x-small;">2.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Beers, TM. “<a href="http://www.bls.gov/opub/mlr/2000/06/art3exc.htm"><span class="Apple-style-span" style="color: magenta;">Flexible schedules and shift work: replacing the “9-to-5” workday?”</span></a>. <i>Monthly Labor Review</i>. (2000). </span><br />
<span style="font-size: x-small;">3.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Awake in Philly Community Education Group. “<a href="http://www.awakeinphilly.org/ExcessiveSleepiness/SWSD_FactSheet.pdf"><span class="Apple-style-span" style="color: magenta;">Fact sheet: shift work sleep disorder</span></a>”. (2004). </span><br />
<span style="font-size: x-small;">4.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>CDC. “<a href="http://www.cdc.gov/Features/dsSleep/"><span class="Apple-style-span" style="color: magenta;">Insufficient sleep is a public health epidemic</span></a>”. (2011). </span><br />
<span style="font-size: x-small;">5.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>US Department of Transportation, National Highway Traffic Safety Administration, National Center on Sleep Disorders Research, National Heart Lung and Blood Institute. “<a href="http://www.nhtsa.gov/people/injury/drowsy_driving1/Drowsy.html#NCSDR/NHTSA"><span class="Apple-style-span" style="color: magenta;">Drowsy driving and automobile crashes</span></a>” (2011). </span><br />
<span style="font-size: x-small;">6.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Bryant, PA., et al. <a href="http://www.nature.com/nri/journal/v4/n6/abs/nri1369.html"><span class="Apple-style-span" style="color: magenta;">“Sick and tired: does sleep have a vital role in the immune system?”</span></a> <i>Nature Reviews Immunology</i>. 4:457-467. (2004). </span><br />
<span style="font-size: x-small;">7.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Toth, LA., et al. <a href="http://iai.asm.org/cgi/content/abstract/56/7/1785"><span class="Apple-style-span" style="color: magenta;">“Alteration of sleep in rabbits by Staphylococcus aureus infection”</span></a>. <i>Infect. Immunity.</i> 58: 1785-1791. (1988). </span><br />
<span style="font-size: x-small;">8.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Born, J., et al. <a href="http://www.jimmunol.org/content/158/9/4454.short"><span class="Apple-style-span" style="color: magenta;">“<i>Effects of sleep and circadian rhythm on human circulating immune cells”</i>.</span></a> <i>Journal of Immunology</i>. 158:4454-4464. (1997). </span><br />
<span style="font-size: x-small;">9.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Everson, CA. <a href="http://ajpregu.physiology.org/content/265/5/R1148.abstract"><span class="Apple-style-span" style="color: magenta;">“Sustained sleep deprivation impairs host defense</span></a>”. <i>Am. J. Physiol. </i>265:R1148-R1154. (1993). </span><br />
<span style="font-size: x-small;">10.<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span>Kripke, DF., et al. <i>“<a href="http://archpsyc.ama-assn.org/cgi/content/full/59/2/131"><span class="Apple-style-span" style="color: magenta;">Mortality associated with sleep duration and insomnia”</span>.<span class="Apple-style-span" style="color: black;"> Arch</span></a>. Gen. Psychiatry.”</i> 59:131-136. (2002).</span></div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com3tag:blogger.com,1999:blog-5699986821429190705.post-21163744925072123832011-06-07T15:35:00.000-07:002011-11-03T13:54:34.985-07:00Think twice before diving into a high-fat diet: New research indicates how saturated fatty acids promote the development of Type 2 Diabetes<style>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">from<a href="http://ryangruss.com/style/funk/displacement/"> <span class="Apple-style-span" style="color: magenta;">ryangruss.com</span></a></span></td></tr>
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<i><b><u>Public Interest Note:</u></b></i></div>
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<span style="font-size: small;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">We hardly need to read or watch the news everyday to observe one of the fastest growing trends in America: obesity. <a href="http://www.cdc.gov/obesity/data/trends.html" style="color: magenta;">Obesity</a> is defined by the Center for Disease Control and Prevention “as a body mass index (BMI) of 30 or greater. BMI is calculated from a person’s weight and height and provides a reasonable indicator of body fatness” According the CDC, nearly every state in the U.S. has populations containing at least 20% obese adults<sup>1</sup>. Of course, obesity does not merely affect Americans, as the World Health Organization estimates </span><a href="http://www.who.int/features/factfiles/obesity/en/" style="color: magenta;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">more than 300 million people aro</span><span class="Apple-style-span" style="font-family: Arial;">und the world are obese</span></a><sup style="font-family: Arial;">2</sup><span class="Apple-style-span" style="font-family: Arial;">.</span></span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">Our friends and family and self-help books tell us that “beauty comes in all shapes and sizes” and we want to believe this. Hearing this makes us feel beautiful no matter what we look like, and we’re lucky to be surrounded by people that will love us unconditionally. But at the same time it’s important to realize that it may not be so beautiful to be dependent on insulin injections to survive, suffering from chronic inflammation and increased susceptibility to infections. The link between obesity and a variety of health concerns including heart disease and diabetes is well established. A <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa0908610" style="color: magenta;">2010 study</a> spearheaded by Kaiser Permanente and published in the <i>New England Journal of Medicine</i> (<i>NEJM</i>) showed that heart disease has dropped significantly-by 24%- between 1999-2008. Much of this decline, the research team noted, is attributable to decreases in cigarette smoking and increases in the use of cardio-protective medications during the course of those years<sup>3</sup>. Importantly, in the same issue of <i>NEJM</i> a perspective editorial by Drs. Jerimiah Brown and Gerald O’Conner, noted that during those same years 1999-2008, the incidence rate for Type 2 Diabetes and obesity increased. They concluded “These trends suggest that we are succeeding some areas by reducing the burden of modifiable risk factors, such as smoking, hypertension, and high cholesterol levels, but that our society’s diabetes and obesity problems are worsening.”<sup>4</sup> The data supporting a link between obesity and diabetes is clear, both of which cause detriment not only to us individuals, but also to our community with increased medical costs, unhealthy workforces and reduced life expectancies.</span></div>
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<span style="font-size: small;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">The role of scientists and doctors is vital and necessary in fighting this disappointing epidemic. In the early 1950’s Dr. Hans Kraus had published a series of provoking research articles regarding the lack of physical activity of Americans, specifically the children. In comparison to European children in a series of physical activity tests, Kraus and colleagues revealed out of 4,400 students (age 6-16) “56 percent of the U.S. students failed at least one of the test components…only about 8% of the European children failed”<sup>5</sup>. These startling data quickly stirred interest among the general public, as people began to consider more the importance of diet and exercise to lead healthy, productive lives. Not only the lives of individuals, but the life of the country as a whole and in 1955 President Eisenhower invited Dr. Kraus for a meeting to establish a course of action based on the data presented. In less than year, the President commissioned the “President’s Council on Youth Fitness” to organize a new initiative called the “Presidential Fitness Awards” in which for school children complete a series of physical fitness tests to receive one of these awards. The program functions still today as a way to fight obesity and helped bolster the “<a href="http://www.letsmove.gov/white-house-task-force-childhood-obesity-report-president" style="color: magenta;">Let’sMove</a>” campaign commissioned by First Lady Michelle Obama as a way to “change the way a generation of kids thinks about food and nutrition” and reduce childhood obesity to 5% by 2030 <sup>6</sup></span>. The achievement lead by Kraus over 50 years ago highlights the value of cross talk between scientists and the public and set into motion America’s growing interest in fitness and healthy lifestyles. </span></div>
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<i><b style="mso-bidi-font-weight: normal;"><u>Type 2 Diabetes: The Immunology Behind the Disease</u></b></i></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">Eating whole foods, balanced meals and small portions play a role in maintaining our figures curvy and toned, while simultaneously regulating body’s ability to function properly. Our bodies need to consume foods for nutritional benefit, but what happens when we eat too much, especially foods high in salt, sugar and fat? The most witnessed observation is the accumulation of weight, in the form of fat, deposits in our bellies contributing to our subcutaneous (just beneath the skin) or visceral (covering our organs) fat tissue. When we think of fat, most of us think of glossy white lining of our T-bone steaks. Although it looks like it serves no better function that to moisten our steaks, our fat tissue is a quite dynamic place to be, especially for an adipocyte. <span style="background-color: white;"> </span><span style="background-color: white;">Adipocytes</span> are the cells that largely make up our fat tissue (anatomically referred to as adipose tissue). These cells are unique compared to all the other cells in our bodies. Adipocytes store fats derived from food and liver metabolism. The storage of fats by these cells are vitally important such that adipose tissue protects our organs and acts as a buffer to help ward off certain <span class="Apple-style-span" style="background-color: white;"><span style="background-color: white;"></span></span>pathogens. Moreover, because the metabolism of fat releases more energy than proteins or carbohydrates, adipose tissue represents the largest energy storage in our bodies. When we eat too much and exercise too little, our adipose tissue increases, literally. As our adipocytes store more and more fat they swell to accommodate the new intake. This of course can be very bad for the rest of our body-most obviously for the organs that lie beneath this mounting fat-which often times is why obesity is linked to a variety of progressive diseases, simply because our diagnostic tools cannot access the affected organ and therefore inhibit many useful prevention strategies to combat such diseases. </span></div>
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<span class="Apple-style-span" style="font-family: Arial;"> </span><span style="font-size: small;"><span class="Apple-style-span" style="font-family: Arial;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> </span></span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">So what does any of this have to with your immune system?</span><span style="font-size: small;"> As I hope you will begin to appreciate, your immune system is an amazing, peculiar system that seems to be involved in nearly every function in your body.</span><span style="font-size: small;"> Least of which includes your fat-or at least how it’s maintained.</span><span style="font-size: small;"> It’s incredible that our bodies have evolved to become vastly dependent upon one, single protein, insulin, with which we wouldn’t be able to focus, our blood pressure would raise uncontrollably-it short, and our body would crash.</span><span style="font-size: small;"> </span><span style="background-color: white; font-size: small;">Insulin</span><span style="font-size: small;"> is a natural hormone produced by beta islet cells in the pancreas in response to increased blood glucose levels.</span><span style="font-size: small;"> The insulin secreted by the pancreas signals through insulin receptors, which are expressed by the cells that regulate our blood glucose levels, largely our liver cells and adipocytes. </span><span style="font-size: small;"> Once insulin has bound to its receptor it activates the adipocytes to absorb any glucose that comes its way, thereby lowering the blood glucose levels and returning the body to homeostasis.</span><span style="font-size: small;"> When the body is unable to produce insulin or becomes unable to respond to insulin-diabetes develops. </span></span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"> Let’s be clear about one thing: your immune system is tightly involved in the development of Diabetes-both Type 1 and Type 2, but in completely different ways. <b><u>Type 1 Diabetes (also known as juvenile diabetes and diabetes mellitus) is an autoimmune disorder.</u></b><b> </b> Recall from the last post that autoimmunity is the result of self-reactive T cells circulating through the body, recognize self-antigen as foreign and trigger the death of any cell expressing that particular antigen. In the case of Type 1 Diabetes, the self-antigen that’s being attacked is insulin-so therefore beta islet cells are under attack by the body’s own immune system. It is for this reason that people diagnosed with this type of diabetes must take insulin shots to balance their blood-glucose levels since they cannot produce insulin independently. Conversely, <b><u>Type 2 Diabetes (T2D) is a metabolic disorder tightly associated with obesity and results in insulin insensitivity</u></b> that is, although the body can make insulin just fine, the adipocytes can’t respond to it and therefore can’t remove lower glucose levels from the blood. Essentially, the body is consuming more sugar and fat than it can regulate, and for reasons incompletely understood, the body loses the ability to recognize all the insulin being produced because of this resulting in hyperglycemia. The role of the immune system is quite evident in the case of Type 1 Diabetes, but it less obvious in the pathology of T2D. </span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"> <span style="font-size: small;">In the 1990’s it was demonstrated that obese tissue released more inflammatory cytokines than lean tissue, thus beginning the investigation of the role inflammation in T2D development <sup>7</sup>.</span><span style="font-size: small;"> <u style="background-color: magenta;"><b style="color: black;">Cytokines</b></u> are small molecules secreted by immune cells that activate the immune system, some cytokines promote inflammation.</span><span style="font-size: small;"> Two of the most studied inflammatory cytokines are TNFalpha and IL-1beta, which are usually released during infections.</span><span style="font-size: small;"> These cytokines are secreted by immune cells once the cell receives instructions to do so.</span><span style="font-size: small;"> Immune cells are able to recognize invading pathogens quickly by recognizing certain pathogen-associated molecular patterns (PAMPs), which are only present on microbes and not our own cells.</span><span style="font-size: small;"> PAMPs stimulate Toll-like receptors (TLRs) and NOD-like receptors (NLRs) to induce TNFalpha and IL-1beta release, respectfully.</span><span style="font-size: small;"> These cytokines are inflammatory because they recruit more immune cells to the site of infection and starts the process of inflammation characterized by swelling, fever, redness, and pain-all of which is required to fight infection.</span><span style="font-size: small;"> This clever detection system allows for the quick response by innate immune cells (macrophages, dendritic cells, and neutrophils) to activate the rest of the immune system to destroy the invading bug.</span><span style="font-size: small;"> Our innate immune cells are the first the cells to respond to an immunological threat. </span><span style="font-size: small;"> </span></span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">Within the past couple decades it was discovered that fat tissue does not merely contain adipocytes, but is full of immune cells too, especially one particular immune cell-the macrophage. The <u style="background-color: magenta;"><b>macrophage</b></u><span style="background-color: magenta;"> </span>is named so because it is one of the largest immune cells and engulfs nearly everything it crosses. You can think of it as the janitorial cell of the body, clearing tissue from cell debris and microbes. Earlier just this year, Vishwa Deep Dixit’s laboratory based at Louisiana State University, <a href="http://www.nature.com/nm/journal/v17/n2/full/nm.2279.html" style="color: magenta;">established a role for fat-associated macrophages in controlling obesity-induced T2D</a><span style="color: magenta;">.</span> They had established a model to study T2D by engineering mice that were deficient for a particular NLR (NLRP3), which is important for IL-1beta release. When these mice were fed a high-fat diet, their blood-glucose levels were lower than their wild-type counterparts. Furthermore, the fat-associated macrophages possessed anti-inflammatory characteristics whereas wild-type mice fed a high-fat diet contained highly inflammatory macrophages within their fat tissue. Moreover, they showed that IL-1beta released by macrophages induce other immune cells to develop insulin resistance and perpetuate the inflammatory response, which ultimately leads to chronic inflammation and T2D <sup>8</sup>. Although, these authors convincingly demonstrated the role of NLRP3-induced IL-1beta in the development of T2D and chronic inflammation, what was directly activating the fat-associated macrophage to produce IL-1beta in the first place remained elusive. </span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">As you’ll recall, macrophages become activated via TLR or NLR stimulation. Macrophages usually require a TLR or NLR activator in order to produce inflammatory cytokines like IL-1beta. So, in the absence of microbial infection (which is the standard activator of these receptors) <i><u>how</u><b> </b></i>do these inflammatory cytokines get released in the fat tissue? What is present in the adipose tissue that activates macrophages to release IL-1beta, a cytokine critically important in the progression of T2D? <i><u>That</u></i> is the great mystery and focus of the research discussed below that was recently published by <a href="http://gmb.unc.edu/faculty/ting.htm" style="color: magenta;">Dr. Jenny Ting's</a> research group at the University of North Carolina, Chapel Hill.</span></div>
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<i><b style="mso-bidi-font-weight: normal;"><u>Treating Diabetes and Obesity: Why This Research Paper Matters:</u></b></i></div>
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<span class="Apple-style-span" style="font-family: Arial;"> </span><span style="font-family: Arial; font-size: small;"> </span><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">The best prevention is clear: exercise daily and eat balanced, small-portioned meals.</span><span style="font-size: small;"> However, in some cases, people are more genetically susceptible in developing the disease or for some individuals, diet and exercise isn’t enough to control the disease.</span><span style="font-size: small;"> For these people, there is little treatment options available.</span><span style="font-size: small;"> Currently, anti-inflammatory diets are popping up on the scene as alternative diet plans to help combat diseases associated with chronic inflammation.</span><span style="font-size: small;"> Such diets are heavy in foods that people should be eating more of regardless of their health conditions: whole vegetables and fruits rich in vitamins and anti-oxidants, which help combat inflammation.</span><span style="font-size: small;"> Although the value of eating such foods is becoming increasingly acknowledged, the mechanisms by which these foods block inflammation is less known.</span><span style="font-size: small;"> For example, although for decades, millions of people take omega-3 fatty acid (fish oil) supplements for its anti-inflammatory properties, it was not until 2010 that a team of researchers identified the exactly how omgea-3 fatty acids were able to dampen inflammation! Not only did these researchers discover the receptor that binds omega-3 fatty acids and that this receptor inhibits TLR-induced pro-inflammatory cytokine release from macrophages, but they also provide incredible data showing that omega-3 fatty acids that bind this receptor promotes insulin sensitivity!<sup>9</sup> This new data suggests the use of omega-3 fatty acid as a possible treatment option specifically for T2D.</span><span style="font-size: small;"> </span><span style="font-size: small;"> As it turns out, many drugs and supplements are prescribed without the knowledge of how the drug actually works.</span><span style="font-size: small;"> There is no doubt that more effective drugs could be available if we better understood the underlying mechanisms behind disease. </span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">As a testament for the work done in mice regarding the role of IL-1beta in T2D pathogenesis, recent clinical trials are underway testing a molecule that blocks IL-1beta</span><span style="font-size: small;"> </span><span style="font-size: small;">signaling, anakinra.</span><span style="font-size: small;"> A 2007 <i>NEJM</i> paper discussing the results of one study using <a href="http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000183/" style="color: magenta;">anakinra</a> showed that it improved glucose levels and reduced system inflammation in patients receiving the drug <sup>10</sup>.</span><span style="font-size: small;"> But again and importantly, this is clinical trials and the need to discover new drug targets and development of novel treatments for T2D is needed to help combat a disease that plagues millions of our parents, friends and increasingly-our children.</span><span style="font-size: small;"> Dr. Jenny Ting’s UNC research group recently published in Nature Immunology compelling data indicating how saturated fats activates a newly identified pathway involved in the development of T2D.</span><span style="font-size: small;"> With this latest discovery, it is likely that their data will bolster many promising new therapeutic targets to utilize in our fight against T2D.</span><b style="mso-bidi-font-weight: normal;"><span style="font-size: small;"> </span> </b></span></div>
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<i><b style="mso-bidi-font-weight: normal;">What the &*%$#! Does the Title Mean?!</b></i></div>
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<span style="font-family: Arial;">Haito Wen, et al.<a href="http://www.nature.com/ni/journal/v12/n5/full/ni.2022.html"><span class="Apple-style-span" style="color: magenta;"> <b>“Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling”</b></span></a><b style="color: magenta;">.</b> <i style="mso-bidi-font-style: normal;">Nature Immunology</i>. 12(5):408-415. (2011).</span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Diagram illustrating NALP3 inflammasome complex. Although a number of stimuli was known to induce inflammation via NALP3 activation (abestos, cholesterol, silica, etc), <b>prior to the research discussed here, fatty acids high in diabetes patients was not known to contribute to inflammation through the same mechanism!</b></span> <span class="Apple-style-span" style="font-size: xx-small;">Image from <a href="http://www.invivogen.com/"><span class="Apple-style-span" style="color: magenta;">www.invivogen.com</span></a></span></td></tr>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">1)<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span></span><span style="background-color: magenta; font-size: small;"><b><u>NLRP3</u></b></span><span style="font-size: small;"><span style="background-color: magenta;"> </span>a type of NLR called-brace yourself-nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 or as it’s more commonly, for obvious reasons, as NLRP3. Although the official name of this protein is a mouthful, it’s highly descriptive of what the protein looks like. Each part of it, each domain is important for its function. Pyrin domains are particularly important for interactions with other intracellular proteins. </span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">2)<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span></span><span style="background-color: magenta; font-size: small;"><b><u>ASC</u></b></span><span style="font-size: small;"><span style="background-color: magenta;"> </span>is a small intracellular protein that happens to also consist of pyrin domains allowing it to bind to NLRP3 very nicely. See, NLRP3 isn’t very useful on its own; it needs ASC to carry out a function. The value of ASC lies with what it brings to NLRP3: an enzyme. Specifically, an enzyme called caspase-1 associates with ASC, so when NLRP3 recruits ASC, it’s recruiting caspase-1 too. Caspase-1 is a very important enzyme for the immune response because it chops up big cytokines into a smaller, more functional fragment that can be secreted by the cell. What kind of cytokines does caspase-1 process? None other than the much-talked-about pro-inflammatory cytokine, IL-1beta. </span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">3)<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> <span style="background-color: magenta;"> </span></span></span><span style="background-color: magenta; font-size: small;"><b><u>Inflammasome</u></b></span><span style="font-size: small;"><span style="background-color: magenta;"> </span>is a term to describe a group of proteins interacting with each other that promote inflammation. The NLRP3-ASC inflammasome therefore refers to the complex containing NLRP3, ASC, and caspase-1. It is known that a wide variety of PAMPs and danger-associated signals activate the formation of this signaling complex. Recently, a lot of work has been done investigating the role of the NLRP3 inflammasome in a variety of infections and injuries. Collectively, it’s now known that the NLRP3 inflammsome is activated in response to stressful conditions (stressful to a cell, that is), like when neighboring cells are dying or during infection. It is important to recall, that in obesity these events are not happening in the adipose tissue, so what the stressful stimuli are is the point of this research paper.</span></span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;"> 4)<span style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> <span style="background-color: magenta;"> </span></span></span><span style="background-color: magenta; font-size: small;"><b><u><span style="background-color: yellow;"><span style="background-color: magenta;">Insulin signaling</span></span> </u></b></span><span style="font-size: small;">refers to what happens when insulin binds its specific receptor. Upon binding to insulin, the insulin receptor recruits another protein called the insulin receptor substrate, which will instruct the cell to survive and divide, to efficiently remove glucose from the blood. The concept with T2D progression is that too much glucose is around such that insulin is being produced by the pancreas all the time in high amounts-which desensitizes adipocytes, so that blood-glucose levels remain high. One likely candidate that causes this effect is impaired insulin receptor signaling. </span></span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">Put all these terms together and we can now infer that: <b style="color: magenta;">Certain fats we eat cause the NLRP3 inflammasome to assemble. The NLRP3 inflammasome contains caspase-1, which will process IL-1beta for release into tissue, which not only promotes inflammation but also blocks insulin receptor signaling, therefore instigating the onset of T2D</b><span style="color: magenta;">. </span></span></div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: Arial;"><i><u>Ready for an adventure? Read on for a guided-tour through the scientific data!</u></i></span></b></div>
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<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;">Palmitate is an example of a saturated fatty acid, common at high levels in obese and T2D patients.</span> <span class="Apple-style-span" style="font-size: xx-small;">Image from <a href="http://www.yellowtang.org/"><span class="Apple-style-span" style="color: magenta;">www.yellowtang.org</span></a></span></td></tr>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">Ok, so we’re not quite ready to dive into the data. We first need to be on the same page about fat. Fat is essential to our well-being. Fat provides most of our energy allowing our bodies to do all the amazing things it needs to do to live. But if there’s one central theme about preventing T2D it’s “excess Let’s all agree that saturated fats are generally pretty bad for us, especially in excess. Saturated fats derive mainly from meats and dairy. Because of their compact structure, if they build up in your arteries a clog can form and increase LDL cholesterol levels. Unsaturated fats are more flexible and come from plants and lower the “bad” LDL cholesterol. The kind of fat used throughout the experiments discussed below is <u style="background-color: white;"><b>palmitate</b></u>, which is an abundant <u>saturated</u> fatty acid in the blood of people who consume a high fat diet <sup>11</sup>, the main culprit of obesity and T2D development. And on that note, let’s dive into the data! </span></div>
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<span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><span style="font-size: small;">The first thing Wen and colleagues logically wanted to determine was whether palmitate could in fact activate the inflammasome, as their title suggests. To do this, they activated macrophages in culture with lipopolysaccharide (LPS), which is required to make what is called “pro-IL-1beta”-the protein that caspase-1 cleaves into mature IL-1b for secretion. If you want to measure IL-1beta released by macrophages stimulated with only LPS, you will hardly find a trace of it. Wen, et al. show that LPS-primed macrophages will secrete loads of IL-1beta when there palmitate around in a time and dose-dependent manner. Furthermore, palmitate only signals IL-1beta release from macrophages that express NLRP3 and ASC as macrophages deficient in either of these proteins significantly reduce the amount of IL-1beta produced. These cytokine effects appear to be NLRP3 inflammasome-specific since when they look at another cytokine (TNFalpha or IL-6), which don’t need caspase-1, palmitate does not affect their secretion. Finally, the authors illustrate, biochemically, that palmitate activates caspase-1 allowing the cleavage of pro-IL-1beta into mature IL-1beta. </span><b><span style="color: magenta; font-size: small;"><span style="background-color: white;">The data is clear: high levels of the saturated fat, palmitate, promotes the release of the pro-inflammatory cytokine IL-1beta via NLRP3-inflammasome dependent mechanism. Amazingly, these effects don’t occur when LPS-primed macrophages are stimulated by unsaturated fatty acids.</span></span></b><span style="font-size: small;"><span style="color: magenta;"> </span>But <i><u>how</u></i> is this happening? Is the saturated fatty acid activating the inflammasome directly or indirectly?</span></span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">As mentioned, when cells are stressed out they signal the NLRP3 inflammasome to assemble and start to secrete inflammatory cytokines to warn the rest of the immune system that something isn’t right and that help is needed. It is well established when cells are stressed, their mitochondria (the energy machine of the cell) loses membrane potential and reactive oxygen species (ROS) start to seep into the cytosol. Furthermore, it’s also known that ROS controls NLRP3 association with ASC and is therefore crucial in inflammasome assembly. </span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">So it makes perfect sense for the authors to investigate whether palmitate can activate ROS. Using a special dye that turns fluorescent in the presence of ROS, Wen, et al. show that palmitate increases ROS generation in cells and that this effect is blocked in the presence of a ROS-inhibitor. Moreover in the presence of palmitate, they showed that IL-1beta is produced, but now-in the presence of this ROS-inhibitor, caspase-1 activity and IL-1beta production greatly diminishes. All together, these data signify a novel finding-and the basis of how this story ended up in <i>Nature Immunology</i>:<span style="color: magenta;"> </span><b style="color: magenta;">palmitate, a fatty acid associated with obesity, causes high levels of IL-1beta production from macrophages by stressing cells to produce ROS and activate the inflammasome.</b> But we have only reached the tip of this iceberg, and many more questions must still be answered to complete this story. One of which is: how do saturated fats stress out cells? </span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">The authors explain that “the AMP-activated protein kinase (AMPK) has emerged as an essential mediator of fatty acid metabolism and it suppresses ROS production” and its activity promotes the development of anti-inflammatory macrophages. The researchers then set out to test their hypothesis that “AMPK plays a role during inflammasome activation by palmitate”. Again, using that ROS-sensitive fluorescent dye, they provide data indicating that activation of AMPK inhibits palmitate-induced ROS production and IL-1beta release. Interestingly, palmitate appears to deactivate AMPK, so that ROS can accumulate in the cell and promote NLRP3 inflammasome assembly and activity. </span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">These data suggest that AMPK activation plays a large role in directing inflammasome activation and that AMPK activity can be exploited by external stimuli like palmitate to promote inflammation. Importantly, this exploitation of AMPK appears to be specific to palmitate and not PAMPs or danger signals associated with injury and infection. This is an important distinction because they way these danger signals induce ROS production is by creating pores in the membrane and opening ion channels. But none of these stresses were induced by palmitate, which begged the question: we now have data that palmitate inhibits an enzyme that blocks ROS, which in effect allows ROS to accumulate in the cell, but how in the world was ROS being generated in the first place by palmitate? </span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">The answer appears to lie in process called <u><b style="background-color: magenta;">autophagy</b></u>, which cells utilize to get rid of old organelles and metabolites for energy. It’s a highly evolutionarily conserved process that is vital in cell survival. More recently, it’s been shown that AMPK positively regulates autophagy during fatty acid metabolism. In the process of metabolizing fatty acids (aka autophagy) a little bit of ROS is generated. Wen, et al. continue to show a number experiments to demonstrate that palmitate deregulates autophagy by inhibiting AMPK. So not only are macrophages highly inflammatory in the presence of unsaturated fatty acids, but their autophagasomal machinery is messed up, which just further perpetuates inflammasome activation. In short, a single stimulus, palmitate can turn a usually anti-inflammatory macrophage (expressing AMPK) to a potent pro-inflammatory macrophage. This would be great news if the plan was to fight a bacterial infection, where inflammatory macrophages are needed to destroy the pathogen, yet in T2D, there isn’t a pathogen and these patients have chronic inflammation, which as this new data suggests is likely due to the high saturated fat diet consumed. Things couldn’t get possibly worse, right?</span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">Of course they can, especially with T2D since we know the disease isn’t solely an inflammatory condition, but also affects the body’s ability sense insulin. So what does all of this palmitate data have to do with that? Wen and colleagues proceed with a series of elegantly designed experiments to investigate the role of palmitate in insulin signaling. First, they show that liver cells pre-treated with IL-1beta are less sensitive to insulin that unprimed cells based on insulin receptor activity. Furthermore, they show this happens because IL-1beta blocks IRS-1 function, the protein responsible for promoting insulin sensitivity and cell survival. Even more compelling was the data in which they illustrate that if they gave media from palmitate-activated macrophages, which would contain IL-1beta, to liver cells, the same effect was observed. </span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">They repeated this experiment with NLRP3 and caspase-1 deficient macrophages, which had no effect on insulin receptor activity suggesting that <b><span style="color: red;"><span style="color: magenta;">palmitate activates macrophages to release IL-1beta in a NLRP3 inflammasome-dependent manner, which can then go on to inhibit insulin signaling in liver cells.</span> </span></b> If you recall, interference of insulin signaling will have detrimental effects for liver and fat cells’ ability to remove glucose from the blood, thereby promoting the development of T2D.</span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">To study this more closely, in regards to T2D, the authors fed mice a high fat diet for 12 weeks and show that compared to mice fed on a low-fat diet, had higher blood-glucose levels. Moreover, mice deficient in IL-1beta, ASC or NLRP3 had glucose levels similar to that of a wild-type mouse on a lean diet! Finally, their in vivo data corroborated their in vitro findings that inflammasome activation within macrophages blocks insulin receptor signaling. Collectively, Dr. Jenny Ting’s research group provided valuable insight how saturated fats control not only our weight, but also our immune system. </span></div>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;">Not only did they provide correlative evidence about palmitate, but the also went the extra mile in terms of experimental proof to identify the mechanism by which palmitate contributes to T2D disease. This is why this particular research is regarded highly by the scientific community and published in high-profile journals. Not only did Wen, et al. convincingly show how palmitate increased IL-1beta production, but the also revealed a promising new set of targets for T2D and chronic inflammatory diseases: autophagy. <b><span class="Apple-style-span" style="color: magenta;">T</span><span style="color: magenta;">his is very exciting research that is bound to play a significant role in supporting the development of future treatment options for the millions of people suffering from such ailments!</span></b> However, as their last figure nicely demonstrates, remember that the best prevention to T2D-even if you’re genetically susceptible- it to maintain a low-fat diet and try to fit in a bit of exercise each day. </span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyv5ZTrwihpF4srm8r6rX_YU8iVAFSG4j9m_8-T1Q4L1w79E0_yD8j5s9e1MoN4JnORXsL6MYon0l9ZQ1MEbmbw8i7vqPEfG3MsdTk6trn8KnjQdgenLaJDnWpVmrIaTJPbniCBnvVYxc/s1600/discovery_medicine_no_62_thirumala-devi_kanneganti_figure_2-274x300.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyv5ZTrwihpF4srm8r6rX_YU8iVAFSG4j9m_8-T1Q4L1w79E0_yD8j5s9e1MoN4JnORXsL6MYon0l9ZQ1MEbmbw8i7vqPEfG3MsdTk6trn8KnjQdgenLaJDnWpVmrIaTJPbniCBnvVYxc/s320/discovery_medicine_no_62_thirumala-devi_kanneganti_figure_2-274x300.png" width="292" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia, 'Times New Roman', serif;"><b>Wen, et al. contributed significant understanding to the inflammatory mechanism behind T2D showing that the fatty acid, palmitate activates the NALP3 inflammasome</b>, enhancing inflammation in adipose tissue and inducing insulin resistance and beta-cell dysfunction</span>. <br /><span class="Apple-style-span" style="font-size: xx-small;">Image from<span class="Apple-style-span" style="color: magenta;"> <a href="http://discoverymedicine.com/"><span class="Apple-style-span" style="color: magenta;">discoverymedicine.com</span></a></span></span></td></tr>
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<span style="font-family: Georgia, 'Times New Roman', serif; font-size: small;"><b>Oh, and one last thing to keep in mind:</b> mice are quite active during the day, roaming around and playing with each other, so it’s likely that the effects shown in this research paper regarding mice kept on a high-fat diet could be greatly exacerbated if the mice were sedentary! On that note, I think I’ll go for a run after work today, maybe you’ll be inspired to do something active too! </span></div>
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<span style="float: left; padding-bottom: 5px; padding-left: 5px; padding-right: 5px; padding-top: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_white.png" style="border: 0;" /></a></span>
<span class="Z3988" style="font-size: x-small;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+immunology&rft_id=info%3Apmid%2F21478880&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Fatty+acid-induced+NLRP3-ASC+inflammasome+activation+interferes+with+insulin+signaling.&rft.issn=1529-2908&rft.date=2011&rft.volume=12&rft.issue=5&rft.spage=408&rft.epage=15&rft.artnum=&rft.au=Wen+H&rft.au=Gris+D&rft.au=Lei+Y&rft.au=Jha+S&rft.au=Zhang+L&rft.au=Huang+MT&rft.au=Brickey+WJ&rft.au=Ting+JP&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Clinical+Research%2C+Pharmacology%2C+Physiology%2C+Genetics%2C+Pathology%2C+Metabolism">Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, & Ting JP (2011). Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. <span style="font-style: italic;">Nature immunology, 12</span> (5), 408-15 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21478880" rev="review"><span class="Apple-style-span" style="color: magenta;">21478880</span></a></span><br />
<i><span style="font-size: x-small;"><b><br /></b></span></i><br />
<i><span style="font-size: x-small;"><b><br /></b></span></i><br />
<span class="Apple-style-span" style="font-size: x-small;"><b><i><br /></i></b></span><br />
<span class="Apple-style-span" style="font-size: x-small;"><b><i><br /></i></b></span><br />
<i><span style="font-size: x-small;"><b>References and Further Reading:</b></span></i><span style="font-size: x-small;"><span style="font-family: Arial;"> </span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">1: Center for Disease Control and Prevention. </span><a href="http://www.cdc.gov/obesity/data/trends.html"><span style="color: magenta; font-family: Arial;">“U.S. Obesity Trends: Trends by State 1985-2009”</span></a><span style="font-family: Arial;"> </span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">2: WHO. <a href="http://www.who.int/features/factfiles/obesity/en/"><span class="Apple-style-span" style="color: magenta;">“WHO Fact Files: Ten facts on obesity</span></a>”. (2010).</span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">3: Yeh, RW., et al. </span><a href="http://www.nejm.org/doi/full/10.1056/NEJMoa0908610"><span style="color: magenta; font-family: Arial;">“Population trends in the incidence and outcomes of acute myocardial infarction”.</span></a><span style="font-family: Arial;"> <i>NEJM.</i> 362:2155-2165. (2010).</span></span><span style="font-size: x-small;"><span style="font-family: Arial;"> </span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">4: Brown, JR and O’Conner, GT. </span><a href="http://www.nejm.org/doi/full/10.1056/NEJMp1003880"><span style="color: magenta; font-family: Arial;">“Coronary heart disease and prevention in the United States”</span></a><span style="font-family: Arial;">. <i>NEJM.</i> 362:2150-2153. (2010).</span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">5:The President’s Council on Physical Fitness and Sports. </span><a href="http://www.fitness.gov/50thanniversary/toolkit-firstfiftyyears.htm"><span style="color: magenta; font-family: Arial;">“History of the President’s Council on Physical Fitness and Sports (1956-2006)</span></a><span style="font-family: Arial;">”.</span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">6: Let’s Move: America’s move to raise a healthier generation of kids. </span><a href="http://www.letsmove.gov/white-house-task-force-childhood-obesity-report-president"><span style="font-family: Arial;"><span class="Apple-style-span" style="color: magenta;">“White House task force on childhood obesity report to the president”. </span><span class="Apple-style-span" style="color: black;">(2010).</span></span></a><span style="font-family: Arial;"> </span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">7: Hotamisligil, GS, et al. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC295872/"><span class="Apple-style-span" style="color: magenta;">“Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance</span></a>”. <i>Journal of Clinical Investigation</i>. 95:2409-2415. (1995).</span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">8: Vandanmagsar, B., et al. “<a href="http://www.nature.com/nm/journal/v17/n2/full/nm.2279.html"><span class="Apple-style-span" style="color: magenta;">The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance</span></a>”. <i>Nature Medicine</i>. 17(2): 179-188. (2011).</span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">9: Oh, DY, et al. <a href="http://www.cell.com/abstract/S0092-8674%2810%2900888-3"><span class="Apple-style-span" style="color: magenta;">“GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects”</span></a>. <i>Cell</i>. 142(5):687-698. (2010).</span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">10:Larsen, CM, et al. “<span class="Apple-style-span" style="color: magenta;"><u>Interleukin-1-receptor antagonist in type 2 diabetes mellitus</u></span>”. <i>NEJM</i>. 356: 1517-1526. (2007).</span></span><br />
<span style="font-size: x-small;"><span style="font-family: Arial;">11: Boden, G., et al. <a href="http://journals.lww.com/co-clinicalnutrition/Abstract/2002/09000/Interaction_between_free_fatty_acids_and_glucose.14.aspx"><span class="Apple-style-span" style="color: magenta;">“Interaction between free fatty acids and glucose metabolism”.</span></a> <i>Curr. Opin. Clin. Nutr. Metab</i>. Care 5: 545-549. (2002).</span></span></div>
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<span style="font-family: Arial;"> </span><span style="font-family: Arial; font-size: 10pt;"></span></div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com5tag:blogger.com,1999:blog-5699986821429190705.post-552419209496766532011-05-13T14:49:00.000-07:002011-11-18T23:04:31.326-08:00Hold the Carrots! Vitamin A May Exacerbate Celiac Disease Symptoms-New study reveals how retinoic acid and IL-15 cooperatively promote gut inflammation<style>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-TkS58fx9EKhc20ec3WML_OyrzQubwaeqwZOy9FhHyug6o5oRpTTkL3brFr1yvfXyvuoYYxNY6CLvo7rIAcdBmHvgS4vOoVbeUb1Wnav-SkGyU3uVrNWYIGo6Vkwm01xtr5X06leADgg/s1600/images.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="290" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-TkS58fx9EKhc20ec3WML_OyrzQubwaeqwZOy9FhHyug6o5oRpTTkL3brFr1yvfXyvuoYYxNY6CLvo7rIAcdBmHvgS4vOoVbeUb1Wnav-SkGyU3uVrNWYIGo6Vkwm01xtr5X06leADgg/s320/images.jpg" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: xx-small;">from <a href="http://pursuitofresearch.org/" style="color: black;">pursuitofresearch.org</a></span></td></tr>
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<u><b><span style="font-size: small;"><i>Public Interest Note: </i></span></b></u></div>
<span style="font-size: small;"><span style="font-family: Arial;"> Chances are either you or someone you know has to be very cautious about the types of food that is eaten. Besides the familiar culprits of <i>Salmonella spp</i>. or <i>E. coli</i>-contaminated foods, millions of Americans must be particularly aware of the foods they consume to prevent violent immune reactions. It is estimated that </span><a href="http://www.aafa.org/display.cfm?id=9&sub=30" style="color: magenta;"><span style="font-family: Arial;">millions of Americans are allergic to certain foods<sup>1</sup></span></a><span style="color: magenta; font-family: Arial;">, </span><a href="http://www.webmd.com/allergies/foods-allergy-intolerance" style="color: magenta;"><span style="font-family: Arial;">10% of the public have food intolerances</span></a><sup><span style="font-family: Arial;">2</span></sup><span style="font-family: Arial;">, and millions suffer from autoimmune diseases triggered by food (</span><a href="http://www.celiac.com/articles/21760/1/Is-Celiac-Disease-Americas-Most-Under-diagnosed-Health-Problem/Page1.html" style="color: magenta;"><span style="font-family: Arial;">3 million alone have Celiac Disease</span></a><sup><span style="font-family: Arial;">3</span></sup><span style="font-family: Arial;">). In the past few years, popular media outlets have increased their coverage regarding food allergies. This trend is most likely in response to the 2010 study published in The Journal of the American Medical Association (JAMA) established that only </span><a href="http://jama.ama-assn.org/content/303/18/1848.short" style="color: magenta;"><span style="font-family: Arial;">8% of children and 5% of adults actually suffer from food allergies</span></a><sup><span style="font-family: Arial;">4</span></sup><span style="font-family: Arial;">. These data came as a shock to the public since it seemed that if anyone off the street could guess the incidence rate of food allergies in America, the majority of people would probably guess closer to 25-50%. The issue of what an allergy is therefore appears to be a fabulous example of how wide the knowledge gap is between scientists and the public (and even some medical doctors). Clearly, there is a lot of confusion out there about how the human body reacts to certain foods. Part of that confusion is because we don’t fully understand the mechanisms that lead or cause such reactions to food. Of particular interest to scientists is to determine what factors cause our immune system to react to food that should be harmless and why some people are more susceptible to these diseases than others. </span></span> <br />
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<b><span style="font-size: small;"><i><u>Tolerating Gluten: The Immunology Behind The Disease</u></i></span></b><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg05AHYSjU-VT6G3vtq_Ic6_Tso1Hz_R0wtnSeyhaEIsA7jfgLDKpe2Y8Cehtb-e8FHLTlaJi9URKBjYN44fR_NoicrZJIaSbSDyXcv-Y2_DOncwPFMc1wZEm6DwnEyf1PXVz9oZj11xkE/s1600/normal-celiac-villi1-300x251.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg05AHYSjU-VT6G3vtq_Ic6_Tso1Hz_R0wtnSeyhaEIsA7jfgLDKpe2Y8Cehtb-e8FHLTlaJi9URKBjYN44fR_NoicrZJIaSbSDyXcv-Y2_DOncwPFMc1wZEm6DwnEyf1PXVz9oZj11xkE/s1600/normal-celiac-villi1-300x251.jpg" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-size: x-small;">Celiac Disease is an AUTOIMMUNE DISORDER, which occurs when there is a break in oral tolerance and the immune system overreacts to gluten by producing highly inflammatory cytokines and inhibiting regulatory T cell function-which results in tissue destruction of the intestines. <b>DePaolo, et al. show new data describing how retinoic acid exacerbates inflammation in the gut due to the high concentration of IL-15 in the guts of Celiac Disease Patients.</b></span> <span class="Apple-style-span" style="font-size: xx-small;">Figure from <a href="http://glutenpost.com/"><span class="Apple-style-span" style="color: magenta;">glutenpost.com</span></a></span></td></tr>
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<span style="font-size: small;"><span style="font-family: Arial;"> Since many people are mistaken that if someone has a reaction to food it must be an allergy, let’s be clear: Celiac Disease IS NOT A FOOD ALLERGY. To be classified as an allergy, individuals produce antibodies much like the ones that are made to fight infections, except food allergy-associated antibodies (IgE) are specific for certain ingredients in food (not pathogens). Circulating IgE antibodies activate mast cells-which release lots of histamine and inflammatory mediators. People with Celiac Disease do NOT produce IgE against gluten, but rather suffer from severe inflammation in their intestines in response to gluten that ultimately leads to an autoimmune reaction that destroys the small intestinal tissue. <b style="background-color: magenta; color: black;"><u>Autoimmunity</u></b><span style="background-color: magenta; color: blue;"> </span>occurs when a person’s own body triggers an immune attack on itself. At this point you might (and should) be thinking: Why would your body react so viciously to something as harmless as wheat? Doesn’t your immune system know any better? </span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">The answer to these questions is multi-faceted and still rigorously evaluated by immunologists. Although there are many factors that contribute to a spectrum of autoimmune disorders, the common theme is that they all cause harm because the body has lost the ability to tolerate itself. Our bodies have evolved to utilize a number of mechanisms to prevent our own immune cells from leading a crusade against our own tissues. Peripheral immune tolerance is the ability of our immune cells being able to become active, inflammatory reactors to pathogens while at the same time ignoring our own proteins or harmless foods we eat. Tolerance can be achieved by deleting auto-reactive immune cells and possessing powerful regulatory cells to inhibit inflammation, both of which help keep our immune systems functioning properly. So when there is a breach of tolerance, we have a problem. That problem is that our bodies become deregulated and can’t distinguish threatening agents from harmless ones. </span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">Think about the last breakfast you ate. Perhaps there was some fruit, toast, and eggs. With each bite you take, you increase the number of foreign substances entering your body. Therefore your guts are one of the most, if not <i>the</i> most, infiltrated organs housing thousands of bits of interlopers for brief moments at a time. Each of these food particulates is seen by your body’s immune system as foreign, as a potential threat to our health, and yet most of us don’t hurl in pain every time we sit down for a meal. Our intestines are full of anti-inflammatory immune cells called T regulatory cells (T<sub>regs</sub>). They are related to the reactive, inflammatory-prone T cells discussed above except T<sub>regs</sub> do not promote inflammation. In fact, T<sub>regs </sub>do quite the opposite. Even when reactive T cells recognize a foreign food protein and begin to initiate an inflammatory response in our intestines (which happens every time we eat), the T<sub>regs</sub> quiet those reactive T cells by producing anti-inflammatory molecules allowing your gut immune cells to essentially ignore the harmless food. This complex regulated system is called <b style="background-color: magenta; color: black;"><u>oral tolerance</u></b><span style="background-color: magenta;">.</span><span style="background-color: magenta;"> </span> For this reason, T<sub>regs</sub> are essential to the maintenance of a healthy, tolerant gut. It is pretty amazing that our bodies have evolved such sophisticated mechanisms to keep us healthy and balanced. Unfortunately, this level of immunological sophistication fails some of us. </span></span></div>
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<b><span style="font-size: small;"><i><span style="font-family: Arial;"><u>Celiac Disease: Current Treatment Options & Why This Research Paper Matters</u></span></i></span></b></div>
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<span style="font-size: small;"><i><span style="font-family: Arial;"> </span></i><span style="font-family: Arial;"> Celiac Disease patients are genetically susceptible individuals who develop inflammatory T cell reactions in their gut in response to gluten. Currently, the only treatment is to live a life completely void of gluten (found in wheat, barley), which is not always easy to do. It has been recently shown that retinoic acid (RA) can increase the number of T<sub>regs</sub> in the gut under homeostatic conditions. The benefits of retinoic acid has been well acknowledged and widely regarded by doctors everywhere for its great anti-inflammatory ability. RA and vitamin A is important for maintaining vision and enhancing skin health because of its anti-inflammatory properties (which is why they are often found in anti-aging crèmes and acne medications). Because vitamin A is naturally abundant in many foods (sweet potatoes, carrots, melons), many doctors and scientists have speculated its use as a treatment for individuals suffering from inflammatory gut diseases such as Celiac Disease<sup>5</sup>.</span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">Since this discovery, some researchers and doctors have speculated the use of RA as a possible treatment for the disease. However, as <a href="http://www.nature.com/nature/journal/v471/n7337/full/nature09849.html" style="color: magenta;">DePaolo, et al. illustrates in their recent <i>Nature</i> paper</a>, RA has a completely different function in a highly inflammatory gut like that seen in Celiac Disease patients and thereby warns against the use of RA as a treatment option for this autoimmune disease.</span></span></div>
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<b><span style="font-size: small;"><i><u>What the &*%$#! Does the Title Mean?!</u></i></span></b></div>
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<span style="font-size: small;"><span style="font-family: Arial;">DePaolo, R.W., et al. <a href="http://www.nature.com/nature/journal/v471/n7337/full/nature09849.html" style="color: magenta;"><b>“Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens”</b></a><span style="color: red;"> </span><i>Nature</i>. 471:220-224. (2011)</span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">1)<span style="font-family: 'Times New Roman'; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span></span><span style="font-family: Arial;">An <b style="background-color: magenta; color: black;"><u>adjuvant</u></b><span style="background-color: magenta;"> </span>is something that boosts the inflammatory response, without an adjuvant T cells activity is too weak to cause much of an inflammatory effect. (Think of <a href="http://escapinganergy.blogspot.com/" style="background-color: white; color: magenta;">anergy</a>! The reason why immune cells become anergic is because they are sub-optimally activated. This happens because the signal they receive is very weak alone, unless that signal is coupled with another which together transforms the quiet immune cell to an active, powerful member of the immune system!) </span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">2)<span style="font-family: 'Times New Roman'; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span></span><span style="color: black;"><span style="font-family: Arial;">IL-15</span></span><span style="font-family: Arial;"><span style="color: blue;"> </span>is a<u style="color: black;"><b> <span style="background-color: magenta;">cytokine</span></b></u><span style="background-color: magenta;">,</span> a small molecule released by an immune cell called dendritic cells (DCs), which help activate T cells. It has been previously demonstrated that individuals with Celiac Disease have a lot more IL-15 than healthy people in their gut<sup>6</sup>. The reason for this remains unknown. </span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">3)<span style="font-family: 'Times New Roman'; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"> </span></span><span style="font-family: Arial;">An</span><b style="background-color: magenta;"><u style="color: black;"><span style="font-family: Arial;"> <span style="background-color: magenta;">antigen</span></span></u></b><span style="font-family: Arial;"><span style="background-color: magenta;"> </span><span style="background-color: magenta;">i</span>s what the immune system recognizes which activates the inflammation. Antigens are proteins that must be processed into smaller pieces called peptides by DCs (dendritic cells are special kind of immune cell that belongs to a very select group of cells appropriately named: Professional Antigen Presenting Cells). The processed antigen is then presented by the APC to activate T cells.</span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">Compile this information together and we can infer that:<i> <b style="color: magenta;">IL-15 acts and RA act cooperatively to induce a powerful inflammatory immune response against antigens that you eat</b><span style="color: magenta;">. </span></i></span></span></div>
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<b><span style="font-size: small;"><i><u>Ready for an adventure? Read on for a guided-tour through the scientific data!</u></i></span></b></div>
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<span style="font-size: small;"><span style="font-family: Arial;">This study was thoroughly designed beginning with the first figure in the paper, which establishes a link between the high levels of IL-15 in the gut and the breach in oral tolerance in Celiac Disease patients. To do this, the researchers isolated DCs and T cells from mice and mixed them together in a culture dish. To this cell culture, they then added TGF-</span><span style="font-family: Symbol;">b</span><span style="font-family: Arial;">eta (an essential cytokine for T<sub>reg </sub>development). When they add TGF-</span><span style="font-family: Symbol;">beta </span><span style="font-family: Arial;">and RA, the number of T<sub>regs </sub>doubles, so clearly RA can substantially promote the development of T<sub>regs</sub>. The purpose of these first experiments is to serve as controls, which provides interesting data, but this information is already known and published previously<sup>7</sup>. So, why is DePaolo and colleagues’ study published in <i>Nature</i>? Because what they show next is what happens when IL-15 is added to the mix-something no one had demonstrated before. Turns out that IL-15 dramatically reduces the number of T<sub>regs</sub> in half, even in the presence of TGF-</span><span style="font-family: Symbol;">b</span><span style="font-family: Arial;">eta! <b><span class="Apple-style-span" style="color: magenta;">What was more amazing was when they added IL-15, TGF-</span></b></span><span class="Apple-style-span" style="color: magenta;"><b><span style="font-family: Symbol;">beta</span></b><b><span style="font-family: Arial;"> and RA to the DC/T cell mixture. The number of T<sub>regs</sub> developed was even more dramatically reduced! Clearly, RA contributes to two completely different outcomes depending on the existence of IL-15</span></b></span><span style="font-family: Arial;"><span class="Apple-style-span" style="color: magenta;">.</span><span style="color: red;"><span style="color: magenta;"> </span> </span>Merely making this connection leaves many questions still unanswered including: Can this effect happen outside of the culture dish and inside a living organism? What’s the mechanism of T<sub>regs</sub> inhibition? and How is all of this connected to Celiac Disease?</span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">Let’s begin with the first question: Does IL-15 act synergistically with RA to inhibit T<sub>regs</sub> development in vivo? To examine the relevance of their experiments with the DC/T cell culture, the scientists fed mice the protein, chicken ovalbumin (OVA), a commonly used and well-accepted model antigen to study oral tolerance in mice. As we would expect, in a wild-type, healthy mouse, T<sub>regs</sub> develop normally in the mesenteric lymph node (MLN-the lymphoid organ in the gut that houses the DCs and T cells). But when they feed OVA to mice that were genetically engineered to overexpress IL-15 in the MLN, number of T<sub>regs</sub> found is reduced in half compared to wild-type mice! </span></span><br />
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<span style="font-size: small;"><span style="font-family: Arial;"> The experiment was then repeated by feeding mice with OVA in the presence of RA and again the mice that had lots of IL-15 present in their gut developed significantly fewer T<sub>regs</sub> than the non-genetically manipulated mice. So it seems that the scientist’s in vitro findings were vindicated in vivo, but they still haven’t demonstrated clearly <i>how</i> this is all happening.</span></span><br />
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<span style="font-size: small;"><span style="font-family: Arial;">It is known the inflammatory cytokines, IL-12 and IFN</span><span style="font-family: Symbol;">gamma</span><span style="font-family: Arial;">, is very important in inhibiting T<sub>reg </sub>development. It is also known that DCs can produce a lot of IL-12 in response to inflammatory stimuli<sup>8</sup>. DePaolo, et al contributed new data to show IL-15 and RA can also induce IL-12 production from DCs. They repeated their OVA-feeding experiments in mice that are unable to produce IL-12. <b style="color: magenta;">In these IL-12-deficient mice, IL-15 and RA do not affect T<sub>reg </sub>development in the gut!</b><span style="color: red;"> </span> Next, they assessed IL-12 levels in the MLN of mice fed OVA, substantially more IL-12 was found in their MLN of IL-15 overexpressing mice than wild-type mice and the amount of IL-12 is even more elevated in mice that were fed OVA and RA. <span class="Apple-style-span" style="color: magenta;"><b>This inflammatory effect can be inhibited when they block either RA or IL-12 signaling</b>.</span><span style="color: magenta;"> </span> To construct a more complete signaling mechanism, they do a series of important molecular biology experiments to figure out which transcription factor is regulating IL-12 production from DCs in the presence of IL-15 and RA. In three figures, the research group convincingly illustrates the mechanism in which DCs respond to IL-15 and RA by producing high levels of IL-12 (via JNK-mediated transcription), which is then secreted and acts on nearby T cells to inhibit their development into T<sub>regs. </sub></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj0de5_M5KY_5AshI1KiGqCPksaCi3YN_3UY234jzAc9CCtlFoA5MW8BXFinAF0z58UaAskiHewEshJ0zfHAxTBNfHxMkKP50pdhGuEUO5g906NMloZnYDBMSt3OWfokZgF3t1JRf6BwuY/s1600/Pathogenesis+of+Celiac+Sprue.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj0de5_M5KY_5AshI1KiGqCPksaCi3YN_3UY234jzAc9CCtlFoA5MW8BXFinAF0z58UaAskiHewEshJ0zfHAxTBNfHxMkKP50pdhGuEUO5g906NMloZnYDBMSt3OWfokZgF3t1JRf6BwuY/s400/Pathogenesis+of+Celiac+Sprue.jpeg" width="321" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span class="Apple-style-span" style="font-family: Georgia,'Times New Roman',serif;">Image depicting the role of MHC molecule, HLA-DQ2 (or 8) contributes to inflammation in the gut via the production of IFNgamma and TNFalpha, which when goes unregulated, leads to tissue destruction in the intestines. </span><span class="Apple-style-span" style="font-size: xx-small;">Image from <a href="http://bio.davidson.edu/"><span class="Apple-style-span" style="color: magenta;">bio.davidson.edu</span></a></span></td></tr>
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<span style="font-size: small;"><span style="font-family: Arial;">Whew! This is a lot of data so far and we are almost at the end of the road-but there’s one more figure that really makes this paper outstanding. The final set of experiments published depicts the novelty of this research. These scientists, for the first time, develop a physiologically relevant mouse model to study Celiac Disease. It is already understood that people can be genetically susceptible to developing Celiac Disease, if they express a certain major histocompatability complex (MHC) on their APCs. The same cells responsible for processing foreign proteins, presents these peptides to T cells via MHC. It has been known that the expression of MHC molecule HLA-DQ8 (or HLA-DQ2) is associated with celiac disease development because both molecules selectively bind gluten peptides tightly<sup>9 </sup>. As with common genetic screening test, just because you express a certain molecule or gene, does not always result in disease development. In fact, 40% of people express either celiac-disease-associated MHC, but only 2% of these individuals develop Celiac Disease<sup>10</sup>. So clearly, HLA-DQ8/-DQ2 is not the only thing contributing to the onset of disease in these patients. DePaolo and colleagues decided to breed their IL-15 overexpressing mice with mice that only express HLA-DQ8 to test the hypothesis that gluten is fed to mice that express HLA-DQ8, the DCs in the gut will process and present gluten peptides via HLA-DQ8 to activate T cells, but because these mice express lots of IL-15 in the gut too, the T cells will not develop into T<sub>regs</sub>. So if T cells get activated, but do not turn into regulatory cells-what happens? When they did this experiment, they observed a quite remarkable effect: <b style="color: red;"><i><span style="color: magenta;">t</span><span style="color: magenta;">he gut T cells turned into inflammatory, IFN</span></i></b></span><b style="color: magenta;"><i><span style="font-family: Symbol;">gamma</span></i></b><b style="color: magenta;"><i><span style="font-family: Arial;">-producing effector T cells in the mice that expressed both HLA-DQ8 and high IL-15.</span></i></b><span style="font-family: Arial;"> The mice that only expressed HLA-DQ8 (low IL-15 levels) did not develop any inflammatory T cells. This effect, consistent with their previous figures, was even more dramatically induced in the presence of RA. Lastly, they correlate these findings with active Celiac Disease patients.</span></span></div>
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<span style="font-size: small;"><span style="font-family: Arial;">In conclusion, what this extraordinary research team provided us with a physiological-relevant mouse model to further study the mechanism of Celiac Disease development in mice, offered insight into the importance and mechanism of not only oral tolerance, but also how gut immunity may be affected in related gut inflammatory conditions such as inflammatory bowel disease. <b style="color: magenta;"><i>Furthermore, this research highlights the important role of tissue environment in determining RA function.</i></b><span style="color: red;"> </span> Before this publication, everywhere people looked-skin, eyes, etc. RA and vitamin A were beneficial agents that promoted anti-inflammation. <b style="color: magenta;"><i>However, in the gut-where IL-15 can reach high levels- RA has a completely different role as an adjuvant that promotes severe inflammation and effector T cell activation. Finally and importantly, this collaborative research effort revealed a promising, new target (IL-15) for the treatment of a disease that has no cure. </i></b></span></span></div>
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<span class="Z3988" style="font-size: x-small;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature&rft_id=info%3Apmid%2F21307853&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Co-adjuvant+effects+of+retinoic+acid+and+IL-15+induce+inflammatory+immunity+to+dietary+antigens.&rft.issn=0028-0836&rft.date=2011&rft.volume=471&rft.issue=7337&rft.spage=220&rft.epage=4&rft.artnum=&rft.au=DePaolo+RW&rft.au=Abadie+V&rft.au=Tang+F&rft.au=Fehlner-Peach+H&rft.au=Hall+JA&rft.au=Wang+W&rft.au=Marietta+EV&rft.au=Kasarda+DD&rft.au=Waldmann+TA&rft.au=Murray+JA&rft.au=Semrad+C&rft.au=Kupfer+SS&rft.au=Belkaid+Y&rft.au=Guandalini+S&rft.au=Jabri+B&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CImmunology%2C+Clinical+Research%2C+Pharmacology%2C+Physiology%2C+Genetics%2C+Pathology%2C+Metabolism">DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, & Jabri B (2011). Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. <span style="font-style: italic;">Nature, 471</span> (7337), 220-4 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21307853" rev="review"><span class="Apple-style-span" style="color: magenta;">21307853</span></a></span><br />
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<b><span style="font-size: x-small;"><span style="font-family: Arial;"><i><span style="font-family: Georgia,'Times New Roman',serif;">References and </span></i></span></span><span class="Apple-style-span" style="font-family: Arial; font-size: x-small;"><i><span style="font-family: Georgia,'Times New Roman',serif;">Further Reading:</span></i></span></b><br />
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<span style="font-size: x-small;"><span style="font-family: Arial;">1: <a href="http://www.aafa.org/display.cfm?id=9&sub=30"><span class="Apple-style-span" style="color: magenta;">“Alergy Facts and Figures”</span>.</a> Asthma and Allergy Foundation of America. </span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">2: <span class="Apple-style-span" style="color: magenta;"><a href="http://www.webmd.com/allergies/foods-allergy-intolerance"><span class="Apple-style-span" style="color: magenta;">“Is It a Food Allergy or Intolerance?”</span></a> </span>WebMd. </span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">3: Adams, Jefferson. <span class="Apple-style-span" style="color: magenta;"><a href="http://www.celiac.com/articles/21760/1/Is-Celiac-Disease-Americas-Most-Under-diagnosed-Health-Problem/Page1.html"><span class="Apple-style-span" style="color: magenta;">“Is Celiac Disease America’s Most Under-Diagnosed Health Problem?</span></a>”</span> Celiac.com: Celiac Disease and Gluten-free Diet Information Since 1995<i>.</i> (2009). </span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">4: Schneider Chafen, Jennifer J., et al. <a href="http://jama.ama-assn.org/content/303/18/1848.short"><span class="Apple-style-span" style="color: magenta;">“Diagnosing and Managing Common Food Allergies: A Systematic Review”</span></a>. <i>The Journal of the American Medical Association.</i> 303(18): 1848-1856. 2010. </span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">5: Mora, J. Rodrigo, et al.<span class="Apple-style-span" style="color: magenta;"> <a href="http://www.nature.com/nri/journal/v8/n9/full/nri2378.html"><span class="Apple-style-span" style="color: magenta;">“Vitamin effects on the immune system: vitamins A and D take center stage”</span></a>.</span> <i>Nature Reviews Immunology.</i> 8, 685-698 (2008). </span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">6: Mention, J.J., et al. <span class="Apple-style-span" style="color: magenta;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/12949719"><span class="Apple-style-span" style="color: magenta;">“Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.”</span></a> </span><i>Gastroenterology</i>. 125, 730-745 (2003).</span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">7: Mucida, D., et al. <a href="http://www.sciencemag.org/content/317/5835/256.full"><span class="Apple-style-span" style="color: magenta;">“Reciprocal Th17 and Regulatory T cell Differentiation Mediated by Retinoic Acid</span></a><span class="Apple-style-span" style="color: magenta;">”</span>. <i>Science</i>. 317:5855, 256-260. (2007)</span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">8: “Caretto, D., et al. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908389/"><span class="Apple-style-span" style="color: magenta;">“Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells</span></a><span class="Apple-style-span" style="color: magenta;">.”</span> <i>J. Immunology</i>. 184, 30-34 (2010.)</span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">9: Lundin, KEA. “<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1773536/"><span class="Apple-style-span" style="color: magenta;">HLA-DQ8 as an Ir gene in celiac disease</span></a>”.<i>Gut</i>. 52(1):7-8 (2003).</span></span></div>
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<span style="font-size: x-small;"><span style="font-family: Arial;">10: DePaolo, R.W., et al. “<a href="http://www.nature.com/nature/journal/v471/n7337/full/nature09849.html"><span class="Apple-style-span" style="color: magenta;">Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens</span></a>” <i>Nature</i>. 471:220-224. (2011)</span></span></div>
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<br /></div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com4tag:blogger.com,1999:blog-5699986821429190705.post-29078214002832784992011-05-10T15:02:00.000-07:002011-05-13T14:51:53.826-07:00Fighting Disease by Escaping Anergy<style>
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<div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif; text-indent: 0.5in;"><span style="font-size: small;">A collaborative study lead by Bana Jabri at The University of Chicago was recently published in <i>Nature</i> that clearly highlights the importance of basic immunological research in the development of effective treatments for celiac disease<sup>1</sup>. </span></div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif;"><br />
</div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif; text-indent: 0.5in;"><span style="font-size: small;">This disease affects millions of individuals around the world and yet there remains no cure or medicine to fight it. I could be discussing any disease: pneumonia, HIV/AIDS, diabetes, inflammatory bowel disease, cancer, rheumatoid arthritis, asthma, etc. The point is this: we don’t truly understand most diseases, whether we have a drug to treat them or not. The drugs or treatments that might work, we don’t always understand how they work, which often leads to dangerous side effects and unforeseen cross-reactions that are difficult to treat. Needless to say a lot of questions remain to be answered regarding human disease. Among which (and probably the most important) is: what causes disease? </span></div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif;"><br />
</div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif;"><span style="font-size: small;"> Most diseases are not well understood beyond the concept that it is a disease because it makes people sick. Of course, we know a lot more about disease than we did say a hundred years ago, but in the U.S. the number of new antibiotics on the market has dropped sharply over the past 30 years<sup>2</sup> and the first FDA-approved drug for lupus (which affects between and 300,000 and 1.5 million Americans) only happened earlier this year<sup>3</sup>. There are a number of reasons for this disappointing trend including human health regulations, economics and policy. However, one major contributor may also be the lack of general understanding by the public, medical and pharmaceutical fields regarding the fundamental issues surrounding human disease. Particularly, the molecular, genetic and immunological studies that bolster our understanding and initiate new discoveries of treatments. </span></div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif;"><br />
</div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif; text-indent: 0.5in;"><span style="font-size: small;">If you are still reading this, you clearly have some interest and desire to know more about the biology that leads to disease-which is the first step in becoming an active individual who can then educate and have intelligent discussions with your family, friends and community to help spread the knowledge and involvement of science in our daily lives. But in order to do all of this, we must escape anergy-which in immunological terms, is the state in which a T cell is sub-optimally activated and therefore unable to actively participate in the immune response. Because of this the anergic T cell is doomed to wander throughout the body quietly, doing essentially nothing. So how do you, like the T cell, become active and prepared to take on whatever health challenge comes your way? </span></div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif; text-indent: 0.5in;"><br />
</div><div class="MsoNormal" style="font-family: Georgia,"Times New Roman",serif; text-indent: 0.5in;"><span style="font-size: small;">The answer lies in the fundamental basis of this blog: to provide a second signal called co-stimulation. Co-stimulation refers to the guiding signal that T cells must receive to strengthen their ability to do all the things a powerful, active T cell can do. I hope that this blog will provide you with material that amplifies your knowledge and innate interest in helping to fight one of the biggest challenges we face: disease. The purpose of this blog is help reverse the process of anergy in our community by getting us psyched about biology behind human health issues so that we can become active members of society and engaged in furthering scientific discovery. The goal of this blog is to help bridge the gap between scientists and non-scientists by showcasing and explaining newly published research studies from the world’s top research journals so that we can, together, create and promote a world that despite disease and infection, we aren’t hospitalized because a mosquito bit us or because our insulin triggers a vicious attack on ourselves or because we ate a sandwich with whole wheat bread. </span></div><div class="MsoNormal" style="text-indent: .5in;"><br />
</div><div class="MsoNormal"><span style="font-size: xx-small;"><sup><span style="font-family: Arial;">1</span></sup><span style="font-family: Arial;">: DePaolo, R.W., et al. “<a href="http://www.nature.com/nature/journal/v471/n7337/full/nature09849.html?WT.ec_id=NATURE-20110310">Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens”</a>. <i>Nature</i>. 471, 220-224. March 10, 2001. </span></span></div><div class="MsoNormal"><span style="font-size: xx-small;"><sup><span style="font-family: Arial;">2</span></sup><span style="font-family: Arial;">: Colson, Abigail. <a href="http://www.extendingthecure.org/publication/antibiotic-pipeline">“Policy responses to the growing threat of antibiotic resistance: The Antibiotic Pipeline”</a>. <i>Extending the Cure.</i> May 2008. </span><a href="http://www.extendingthecure.org/publication/antibiotic-pipeline"><span style="font-family: Arial;"></span></a></span></div><div class="MsoNormal"><span style="font-size: xx-small;"><sup><span style="font-family: Arial;">3</span></sup><span style="font-family: Arial;">: Jefferson, Erica. <a href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm">“FDA approves Benlysta to treat lupus”.</a> <i>F.D.A. U.S. Food and Drug Administration: FDA News Release</i>. March 9, 2011. </span></span></div><div class="MsoNormal"><br />
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</div>Heatherhttp://www.blogger.com/profile/06137625705489244444noreply@blogger.com4