Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes

Hill, Natasha J, Stotland, Aleksander, Solomon, Michelle, Secrest, Patrick, Getzoff, Elizabeth and Sarvetnick, Nora (2007) Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in Type 1 diabetes. Biology Direct, 2, p. 5. ISSN (online) 1745-6150

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Abstract

Type 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet beta 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 Idd9 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 beta cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD beta cells is altered. TNFR2 lies within the candidate Idd9 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.

Item Type: Article
Additional Information: This work was supported by the Whittier Diabetes Foundation, Juvenile Diabetes Foundation and National Institutes of Health Grants [DK57644 and DK54063].
Research Area: Biological sciences
Faculty, School or Research Centre: Faculty of Science (until 2011) > School of Life Sciences
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Depositing User: Natasha Hill
Date Deposited: 15 Jun 2017 14:05
Last Modified: 15 Jun 2017 15:12
URI: http://eprints.kingston.ac.uk/id/eprint/38352

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