SUBCONGENIC ANALYSIS OF THE IDD13 LOCUS IN NOD LT MICE - EVIDENCE FORSEVERAL SUSCEPTIBILITY GENES INCLUDING A POSSIBLE DIABETOGENIC ROLE FOR BETA(2)-MICROGLOBULIN/

Although they share similar to 88% of their genome with NOD mice inclu ding the H2(g7) haplotype, NOR mice remain free of T cell-mediated aut oimmune diabetes (IDDM), due to non-MHC genes of C57BLKS/J (BKS) origi n, NOR IDDM resistance was previously found to be largely controlled b y the Idd13 locus within an similar to 24 chi segment on Chromosome 2 encompassing BKS-derived alleles for H3a, B2m, III? and Pcna. NOD stoc ks carrying subcongenic intervals of NOR Chromosome 2 were utilized to more finely map and determine possible functions of Idd13. NOR-derive d H3a-II1 (similar to 6.0 cM) and II1-Pcna (similar to 1.2 cM) interva ls both contribute components of IDDM resistance, Hence, the Idd13 loc us is more complex than originally thought, since it consists of at le ast two genes, B2m variants within the H3a-II1 interval may represent one of these, Monoclonal Ab binding demonstrated that dimerizing with the beta(2)m(2) (NOD type) vs beta(2)m(b) isoform (NOR type alters the structural conformation, but not total expression levels of H2(g7) cl ass I molecules (e.g. K-d, D-b), beta(2)m-induced alterations in H2(g7 ) class I conformation may partially explain findings from bone marrow chimera analyses that ldd13 modulates IDDM development at the level o f non-hematopoietically derived cell types controlling selection of di abetogenic T cells and/or pancreatic beta cells targeted by these effe ctors. Since trans-interactions between relatively common and function ally normal allelic variants mag contribute to IDDM in NOD mice, the s earch for Idd genes in humans should not be limited to functionally de fective variants.