The influence of the major histocompatibility complex on development of autoimmune diabetes in RIP-B7.1 mice.
The most important genetic susceptibility factor for type 1 diabetes is encoded in the major histocompatibility complex (MHC). The nonobese diabetic (NOD) mouse, which develops spontaneous diabetes, expresses H-2g7 comprising the MHC class I molecules Kd and Db and the MHC class II molecule I-Ag7. However, neither B6.H-2g7 mice, in which H-2g7 is expressed on the C57BL/6 genetic background, nor the nonobese resistant (NOR) mouse, in which H-2g7 is expressed on a genetic background that is 88% similar to NOD mice, develop diabetes. Immune tolerance can be broken in these diabetes-resistant mice expressing H-2g7 if the costimulatory molecule B7.1 is present on the islet beta cells. This does not occur if only single MHC class I components of the H-2g7 haplotype are present, such as Kd in BALB/c mice or Db in C57BL/6 mice, both of which develop only a low level of diabetes when B7.1 is expressed. The presence of I-Ag7 leads to the development of an autoimmune T-cell repertoire, and local costimulation of CD8 T-cells precipitates aggressive diabetes. This implies that a major role of the MHC class II molecules in diabetes is the development of an autoreactive T-cell repertoire.
Department of Pathology and Microbiology, Section of Endocrinology, Yale School of Medicine, 333 Cedar St., Mail Box 208020, New Haven, CT 06510, USA.
F Susan
FS
Wong
Wei
W
Du
Ian J
IJ
Thomas
Li
L
Wen
D019264:Adoptive Transfer; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID
D018122:B7-1 Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II