Abstract

The major histocompatibility complex (MHC) has long been associated with predisposition to several autoimmune diseases, including type 1 diabetes and autoimmune thyroiditis. In type 1 diabetes, a primary role has been assigned to class II genes, both in humans and in the nonobese diabetic (NOD) mouse model. However, an involvement of other tightly linked genes is strongly suspected. Here, through two independent sets of experiments, we provide solid evidence for the existence of at least one such gene. First, using a new recombinant congenic NOD strain, R114, we definitively individualized the Idd16 locus from the MHC in a 6-cM interval proximal to H2-K. It affords almost complete protection against diabetes and is associated with delayed insulitis. Second, by genome scan, we mapped non-H2 genes associated with the highly penetrant form of chronic experimental autoimmune thyroiditis (EAT) that is elicited in NOD and NOD.H2^k mice by immunization with thyroglobulin. We identified one major dominant locus, Ceat1, on chromosome 17, overlapping with Idd16. Most importantly, R114 recombinant congenic mice challenged with thyroglobulin did not develop chronic EAT. This new major region defined by both Idd16 and Ceat1 might thus concur to the unique strength of the MHC in autoimmune susceptibility of NOD mice.