GENETIC-CONTROL OF AUTOIMMUNE DIABETES IN THE NOD MOUSE

The nonobese diabetic (NOD) mouse is a model of human autoimmune insul in-dependent diabetes mellitus. The NOD mouse also serves as a model f or studying complex polygenic diseases because at least fourteen diffe rent loci are linked to disease development. The first Idd locus recog nized, Idd1, is linked to the major histocompatibility complex (MHC), and its inheritance and expression are a paradigm for the other non-MH C Idd genes. The NOD allele at Idd1 does not behave as a recessive dia betes susceptibility gene, as it was originally thought to be, but ins tead it acts as a dominant gene with varying degrees of penetrance for the phenotypes of insulitis, a prediabetic inflammatory lesion, and s pontaneous diabetes. MHC congenic strains of mice have shown that the NOD MHC is essential but, by itself, not sufficient for developing dia betes. The contributions of non-MHC Idd loci have also been assessed w ith NOD congenic strains derived by replacing NOD-specific chromosomal segments with those from diabetes-resistant strains of mice. While on ly partial protection from disease is provided by resistance alleles a t single non-MHC Idd1oci, epistatic interaction between two of the loc i, Idd3 and Idd10, produced nearly complete protection from diabetes. Identifying Idd genes and defining their biologic functions should fur ther our understanding of autoimmune disease pathogenesis and facilita te development of new treatments for diabetes.