Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice.
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.
Tisch
R
R
Department of Microbiology and Immunology, Stanford University Medical Center, California 94305.
Yang
X D
XD
Singer
S M
SM
Liblau
R S
RS
Fugger
L
L
McDevitt
H O
HO
D000375:Aging / Q000276:immunology; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007165:Immunosuppression Therapy; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D007527:Isoenzymes / Q000276:immunology; D008214:Lymphocytes; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D007527:Isoenzymes; D005968:Glutamate Decarboxylase