Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes
2007
Secrest Patrick | Solomon Michelle | Stotland Aleksandr | Hill Natasha J | Getzoff Elizabeth | Sarvetnick Nora
<p>Abstract</p> <p/> <p>Type 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet β cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at the <it>Idd9 </it>diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction. Susceptible islets exhibit hyper-responsiveness to inflammatory cytokines resulting in enhanced cell death and increased expression of the death receptor Fas. Fas upregulation in β cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD β cells is altered. <it>TNFR2 </it>lies within the candidate <it>Idd9 </it>interval and the diabetes-associated variant contains a mutation adjacent to the TRAF2 binding site. A component of diabetes susceptibility may therefore be determined by the target of the autoimmune response, and protective TNFR2 signaling in islets inhibit early cytokine-induced damage required for the development of destructive autoimmunity.</p> <p>Reviewers</p> <p>This article was reviewed by Matthiasvon Herrath, HaraldVon Boehmer, and Ciriaco Piccirillo (nominated by Ethan Shevach).</p>
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