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The Influence of the Major Histocompatibility Complex on Development of Autoimmune Diabetes in RIP-B7.1 Mice

¹ Department of Pathology and Microbiology, School of Medical Sciences, University Walk, University of Bristol, Bristol, U.K
² Department of Internal Medicine, Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut

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-2^g7 comprising the MHC class I molecules K^d and D^b and the MHC class II molecule I-A^g7. However, neither B6.H-2^g7 mice, in which H-2^g7 is expressed on the C57BL/6 genetic background, nor the nonobese resistant (NOR) mouse, in which H-2^g7 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-2^g7 if the costimulatory molecule B7.1 is present on the islet ß cells. This does not occur if only single MHC class I components of the H-2^g7 haplotype are present, such as K^d in BALB/c mice or D^b in C57BL/6 mice, both of which develop only a low level of diabetes when B7.1 is expressed. The presence of I-A^g7 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.

Abbreviations: MHC, major histocompatibility complex; RIP, rat insulin promoter

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