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

Natasha J. Hill, Aleksandr Stotland, Michelle Solomon, Patrick Secrest, Elizabeth Getzoff, Nora Sarvetnick

Research output: Contribution to journalReview article

17 Scopus citations

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.

Original languageEnglish (US)
Article number5
JournalBiology direct
Volume2
DOIs
Publication statusPublished - Jan 25 2007

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ASJC Scopus subject areas

  • Immunology
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

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