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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2020-01-07T00:00:00-05:00" class="date-display-single">January 7, 2020</span></p><div class='syndicate'><h1>Researchers find cause of new autoinflammatory disease</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<li>Researchers found that mutations in a specific gene cause a previously unknown autoinflammatory disease, which they’ve named CRIA syndrome.</li>
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<li>Inhibitors targeting the gene’s effects could lead to new treatments for CRIA syndrome and other inflammatory conditions.</li>
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</ul></div><div class="media-float-right"><div class="ds-1col file file-image file-image-jpeg view-mode-floated_media clearfix">
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2020/20200107-cria.jpg?itok=kB4j3NnG&timestamp=1578406328 1x" media="screen and (min-width: 960px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2020/20200107-cria.jpg?itok=JmWUDMNv&timestamp=1578406328 1x" media="screen and (min-width: 800px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium-small/public/news-events/research-matters/2020/20200107-cria.jpg?itok=JUe7Bfd9&timestamp=1578406328 1x" media="screen and (min-width: 600px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-small/public/news-events/research-matters/2020/20200107-cria.jpg?itok=0Q_EWITu&timestamp=1578406328 1x" media="screen and (min-width: 480px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-tiny/public/news-events/research-matters/2020/20200107-cria.jpg?itok=MVPX2z0c&timestamp=1578406328 1x" media="screen and (min-width: 0)" />
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2020/20200107-cria.jpg?itok=JmWUDMNv&timestamp=1578406328" alt="Father and toddler consulting with doctor" title="Father and toddler consulting with doctor" />
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</picture><span class="caption">Identification of a previously unknown autoinflammatory disease—and the mechanism that causes it—could lead to new treatments for this and other inflammatory conditions.</span><span class="credit">Weekend Images Inc. / E+ via Getty Images Plus</span></div>
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</div><p>Autoinflammatory diseases are caused by the immune system—the body’s disease defense that fights off viruses, bacteria, and infection—attacking your body by mistake. That can cause a fever, rash, muscle aches, joint and other tissue swelling, and organ problems.</p>
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<p>Members of three families came to NIH’s Clinical Center with symptoms similar to those caused by an autoinflammatory disease, but with no known cause. The seven patients ranged from 10 to 82 years old. Their symptoms included fevers, swollen lymph nodes, severe abdominal pain, gastrointestinal problems, headaches and, in some cases, abnormally enlarged spleen and liver. Although their condition isn’t life-threatening, they can have persistent fever and swollen lymph nodes from childhood to old age, as well as other symptoms that can lead to lifelong pain and disability.</p>
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||
<p>A team of researchers led by Dr. Daniel Kastner of NIH’s National Human Genome Research Institute (NHGRI) and Dr. John Silke at the Walter and Eliza Hall Institute in Australia carried out a study looking for the cause of the syndrome. After ruling out infections and cancer, they sought answers by genomic sequencing. The study, which was funded by several NIH components, was published on January 2, 2020, in <em>Nature</em>.</p>
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||
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||
<p>The team discovered only one gene—<em>RIPK1</em>—that was consistently different in all patients. Each of the three families had its own unique mutation affecting the very same DNA letter in the <em>RIPK1</em> gene. Each affected person had one mutant and one normal copy of the gene, while unaffected family members had two normal copies.</p>
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<p>The protein encoded by the <em>RIPK1</em> gene is involved in inflammation and programmed cell death—the process by which old cells die so they can be replaced by new ones. Each of the patients’ mutations occur at the location where RIPK1 can be cleaved to prevent it from initiating inflammation and cell death. Thus, Kastner’s team named the disease cleavage-resistant RIPK1-induced autoinflammatory, or CRIA, syndrome.</p>
|
||
|
||
<p>Mouse embryos with two mutant copies of <em>RIPK1</em> did not survive in the uterus due to excessive cell death signals. However, mice with one mutant copy and one normal copy, like the CRIA patients, were mostly normal but had heightened inflammatory responses.</p>
|
||
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||
<p>The team tested therapies known to reduce inflammation in seven patients with CRIA syndrome. While drugs such as etanercept and anakinra, which are used to treat autoinflammatory and chronic diseases such as rheumatoid arthritis, had little effect, one drug called tocilizumab did. Tocilizumab is a drug that suppresses a specific signaling molecule in the immune system. It reduced the severity and frequency of CRIA syndrome symptoms in five out of the seven patients—in some cases with life-changing effects.</p>
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<p>“This discovery underscores the tremendous power of combining astute clinical observation, state-of-the-art DNA sequencing, and the sharing of sequence data in large publicly-accessible databases,” Kastner says.</p>
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||
<p>Researchers are now trying to understand the molecular mechanism that enables tocilizumab to treat CRIA syndrome. Specific inhibitors of RIPK1, which are under development, may also hold promise in both CRIA syndrome and other seemingly intractable inflammatory conditions.</p></div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nih.gov/news-events/nih-research-matters/gut-microbe-drives-autoimmunity" target="_top">Gut Microbe Drives Autoimmunity</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/gene-linked-rare-inflammatory-disease-children" target="_top">Gene Linked to Rare Inflammatory Disease in Children</a></li><li><a href="https://www.niams.nih.gov/health-topics/autoinflammatory-diseases" target="_top">Autoinflammatory Diseases</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="https://www.ncbi.nlm.nih.gov/pubmed/31827281">Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.</a> Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL, Chau D, Liu L, Stoffels M, Kratina T, Lawlor KE, Zaal KJM, Hoffmann PM, Etemadi N, Shield-Artin K, Biben C, Tsai WL, Blake MD, Kuehn HS, Yang D, Anderton H, Silke N, Wachsmuth L, Zheng L, Moura NS, Beck DB, Gutierrez-Cruz G, Ombrello AK, Pinto-Patarroyo GP, Kueh AJ, Herold MJ, Hall C, Wang H, Chae JJ, Dmitrieva NI, McKenzie M, Light A, Barham BK, Jones A, Romeo TM, Zhou Q, Aksentijevich I, Mullikin JC, Gross AJ, Shum AK, Hawkins ED, Masters SL, Lenardo MJ, Boehm M, Rosenzweig SD, Pasparakis M, Voss AK, Gadina M, Kastner DL, Silke J. <em>Nature</em>. 2020 Jan;577(7788):103-108. doi: 10.1038/s41586-019-1828-5. Epub 2019 Dec 11. PMID: 31827281.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Human Genome Research Institute (NHGRI), Intramural Research Program (IRP), NIH Clinical Center (CC), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Allergy and Infectious Diseases (NIAID), and National Heart, Lung, and Blood Institute (NHLBI); European Research Council; Australian National Health and Medical Research Council; Stafford Fox Foundation; Victorian State Government; Australian Cancer Research Fund; Cancer Australia; Cure Cancer Australia Foundation; Victorian Cancer Agency.</p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/research-context-can-we-slow-aging">Research in Context: Can we slow aging?</a></p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/risk-future-burden-dementia-united-states">Risk and future burden of dementia in the United States </a></p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/complete-wiring-map-adult-fruit-fly-brain">Complete wiring map of an adult fruit fly brain</a></p>
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<p><strong>Editor:</strong> Harrison Wein, Ph.D.</p>
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<p><strong><em>NIH Research Matters </em></strong>is a weekly update of NIH research highlights reviewed by NIH’s experts. It's published by the <a href="/institutes-nih/nih-office-director/office-communications-public-liaison">Office of Communications and Public Liaison</a> in the <a href="/institutes-nih/nih-office-director">NIH Office of the Director</a>.</p>
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