Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis

Insulin-dependent diabetes mellitus (IDDM) is a polygenic disease caused by progressive autoimmune infiltration (insulitis) of the pancreatic islets o f Langerhan, culminating in the destruction of insulin-producing beta cells . Genome scans of families with diabetes suggest that multiple loci make in cremental contributions to disease susceptibility. However, only the IDDM1 locus is well characterized, at a molecular and functional level, as allele ic variants of the major histocompatibility complex (MHC) class II HLA-DQB1 , DRB1, and DPB1 genes that mediate antigen presentation to T cells. In the nonobese diabetic (NOD) mouse model, the Idd1 locus was shown to be the or thologous MHC gene I-Ab. Inheritance of susceptibility alleles at IDDM1/Idd 1 is insufficient for disease development in humans and NOD mice. However, the identities and functions of the remaining diabetes loci (Idd2-Idd19 in NOD mice) are largely undefined. A crucial limitation in previous genetic l inkage studies of this disease has been reliance on a single complex phenot ype-diabetes that displays low penetrance and is of limited utility for hig h-resolution genetic mapping. Using the NOD model, we have identified an ea rly step in diabetes pathogenesis that behaves as a highly penetrant trait. We report that NOD-derived alleles at both the Idd5 and Idd13 loci regulat e a T lymphocyte-dependent progression from a benign to a destructive stage of insulitis. Human chromosomal regions orthologous to the Idd5 and -13 in tervals are also linked to diabetes risk, suggesting that conserved genes e ncoded at these loci are central regulators of disease pathogenesis. These data are the first to reveal a role for individual non-MHC Idd loci in a sp ecific, critical step in diabetes pathogenesis-T cell recruitment to islet lesions driving destructive inflammation. Importantly, identification of in termediate phenotypes in complex disease pathogenesis provides the tools re quired to progress toward gene identification at these loci.