Major histocompatibility complex association of insulin-dependent diabetes in the BB rat

BB rats spontaneously develop an insulin-dependent diabetes mellitus strikingly similar to the syndrome observed in man. The disorder requires the presence of multiple susceptibility genes and unknown environmental factors. At least one susceptibility gene resides within the u haplotype of the rat major histocompatibility complex (RT1). Restriction fragment length polymorphism analysis of genomic DNA from rats generated from a series of intercrosses between diabetic BB rats and Buffalo rats (RT1$ sp{ rm b})$ demonstrated that animals heterozygous throughout the RT1 developed IDDM. A single dose of the high risk allele was thus shown to be sufficient for the development of IDDM if other susceptibility factors are present. RFLP analysis of DNA from rats generated in three other breeding studies involving the r8 and r4 recombinant haplotypes mapped the IDDM susceptibility genes between the RT1.A and RT1.C loci, the immune response region. As the u regions of the various haplotypes used in these studies were not derived from the BB rat, the development of IDDM in the progeny strongly suggested that the MHC requirement for IDDM is only for a "u" allele and not a particular or "diabetogenic" u allele.Analysis of the expression of MHC genes in isolated islets of age-matched BB and Wistar-Furth rats demonstrated enhanced class I MHC gene expression in the islets of prediabetic BB rats. Immunohistochemical analysis confirmed that enhanced class I expression was an early event during the pathogenesis of IDDM, and did not detect aberrant expression of class II antigen on beta cells. Investigation of the inducibility of class I and II MHC genes on the rat insulinoma cell line RIN5F by crude lymphokine preparations or recombinant gamma-interferon indicated that although both classes of genes were inducible, their kinetics of induction are quite different. In vitro nuclear transcriptions demonstrated that induction of the genes had a transcriptional basis. Although class II genes were induced by gamma-interferon, class II antigen was not detected by flow cytometric analysis