Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice

Nature. 1993 Nov 4;366(6450):72-5. doi: 10.1038/366072a0.

Abstract

Knowing the autoantigen target(s) in an organ-specific autoimmune disease is essential to understanding its pathogenesis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the islets of Langerhans (insulitis) and destruction of insulin-secreting pancreatic beta-cells. Several beta-cell proteins have been identified as autoantigens, but their importance in the diabetogenic process is not known. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM. Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a panel of five murine beta-cell antigens and find that antibody and T-cell responses specific for the two isoforms of glutamic acid decarboxylase (GAD) are first detected in 4-week-old NOD mice. This GAD-specific reactivity coincides with the earliest detectable response to an islet extract, and with the onset of insulitis. Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes. These results indicate that the spontaneous response to beta-cell antigens arises very early in life and that the anti-GAD immune response has a critical role in the disease process during this period.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / immunology
  • Animals
  • Autoantigens / immunology*
  • Cell Movement / immunology
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology*
  • Female
  • Glutamate Decarboxylase / immunology*
  • Immunosuppression
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Isoenzymes / immunology
  • Lymphocytes
  • Mice
  • Mice, Inbred NOD
  • Mice, Inbred Strains
  • T-Lymphocytes / immunology

Substances

  • Autoantigens
  • Isoenzymes
  • Glutamate Decarboxylase