Research

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

Natasha J Hill^1,3 , Aleksandr Stotland¹ , Michelle Solomon¹ , Patrick Secrest¹ , Elizabeth Getzoff² and Nora Sarvetnick¹

¹  Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

²  Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

³  Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Sciences, Barts and the London Queen Mary's School of Medicine and Dentistry, London, UK

author email corresponding author email

Biology Direct 2007, 2:5doi:10.1186/1745-6150-2-5

Published:	25 January 2007

Abstract

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 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 β cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD β 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.

Reviewers

This article was reviewed by Matthiasvon Herrath, HaraldVon Boehmer, and Ciriaco Piccirillo (nominated by Ethan Shevach).