GENETICS OF THE BB RAT - ASSOCIATION OF AUTOIMMUNE DISORDERS (DIABETES, INSULITIS, AND THYROIDITIS) WITH LYMPHOPENIA AND MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II

The BB/Wor rat develops spontaneous autoimmune diabetes mellitus and a lso frequently develops lymphocytic thyroiditis. To clarify the role o f T cell lymphopenia and the major histocompatibility complex (MHC) in the development of these autoimmune disorders, we studied back-cross animals between the inbred thyroiditis and diabetes-prone BBNB/Wor sub line (MHC RT1.A(u)B(u)D(u)C(u)) and three nonlymphopenic MHC-congenic rat strains: PVG.RT1(u) (RT1.A(u)B(u)D(u)C(u)), PVG.R8 (RT1.A(a)B(u)D( u)C(u)), and PVG.R23 (RT1.A(u)B(u)D(u)C(av1)). We observed that 1) lym phopenia is absolutely required for the development of spontaneous dia betes and insulitis, and is usually associated with the development of thyroiditis; 2) the MHC region to the right of the class I RT1.A locu s is strongly correlated with diabetes and insulitis; and 3) this regi on is also significantly associated with the development of thyroiditi s, but the susceptibility of certain MHC class II alleles (u and a) fo r disease development is distinct for insulitis and thyroiditis. Furth ermore, no recombination was observed between lymphopenia (lyp) and th e neuropeptide Y (Npy) gene polymorphism, which confirmed that lyp map s very close to Npy. The present data suggest that spontaneous insulit is and thyroiditis in the BB/Wor rat develop through common immune def ects involving T cell lymphopenia, but do not always segregate togethe r due to disease-specific interactions with the MHC class II-linked ge nes.