Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant.
Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance.
Serreze
D V
DV
Jackson Laboratory, Bar Harbor, ME 04609.
Leiter
E H
EH
Christianson
G J
GJ
Greiner
D
D
Roopenian
D C
DC
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D001483:Base Sequence; D016827:CD8 Antigens / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics
D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D007328:Insulin; D001613:beta 2-Microglobulin