Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for beta 2-microglobulin.
Although they share approximately 88% of their genome with NOD mice including the H2g7 haplotype, NOR mice remain free of T cell-mediated autoimmune diabetes (IDDM), due to non-MHC genes of C57BLKS/J (BKS) origin. NOR IDDM resistance was previously found to be largely controlled by the Idd13 locus within an approximately 24 cM segment on Chromosome 2 encompassing BKS-derived alleles for H3a, B2m, Il1, and Pcna. NOD stocks carrying subcongenic intervals of NOR Chromosome 2 were utilized to more finely map and determine possible functions of Idd13. NOR- derived H3a-Il1 (approximately 6.0 cM) and Il1-Pcna (approximately 1.2 cM) intervals both contribute components of IDDM resistance. Hence, the Idd13 locus is more complex than originally thought, since it consists of at least two genes. B2m variants within the H3a-Il1 interval may represent one of these. Monoclonal Ab binding demonstrated that dimerizing with the beta 2m(a) (NOD type) vs beta 2m(b) isoform (NOR type) alters the structural conformation, but not total expression levels of H2g7 class I molecules (e.g. Kd, Db). Beta 2m-induced alterations in H2g7 class I conformation may partially explain findings from bone marrow chimera analyses that Idd13 modulates IDDM development at the level of non-hematopoietically derived cell types controlling selection of diabetogenic T cells and/or pancreatic beta cells targeted by these effectors. Since trans-interactions between relatively common and functionally normal allelic variants may contribute to IDDM in NOD mice, the search for Idd genes in humans should not be limited to functionally defective variants.
Serreze
D V
DV
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Bridgett
M
M
Chapman
H D
HD
Chen
E
E
Richard
S D
SD
Leiter
E H
EH
D000483:Alleles; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D019281:Dimerization; D004198:Disease Susceptibility; D005260:Female; D005819:Genetic Markers / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D007536:Isomerism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D011487:Protein Conformation; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D005819:Genetic Markers; D006183:H-2 Antigens; D001613:beta 2-Microglobulin; D007371:Interferon-gamma