Major histocompatibility complex restriction fragment length polymorphisms define three diabetogenic haplotypes in bb and bbn rats

BB rats spontaneously develop insulin-dependent, ketosis-prone diabetes mellitus (DM)) Their disease is of autoimmune etiology, since it is characterized by: (a) lymphocytic and rnacrophage inflammation of pancreatic islets (1), (b) circulating autoantibodies that bind to pancreatic islets of Langerhans (2), (c) increased incidence of Ia antigen-bearing T lymphocytes associated with the development of diabetes (3), (d) progressive and selective destruction of insulin-producing beta ceils (1, 4), (e) the ability to transfer disease to immunodeficient animals with concanavalin A-activated splenic lymphocytes (5), and (f) selective destruction of beta cells in transplanted islets (6); in addition, it can be prevented with many forms of immunotherapy (7). BB rats also exhibit a profound T cell lymphocytopenia with an almost total lack of circulating T lymphocytes, although their thymocytes are normal in number and cell surface phenotype (8). In breeding studies, we and others (9, 10) have shown that at least two genes contribute to the development of diabetes in the BB rat. One is autosomal recessive and determines the profound T cell immunodeficiency present in affected rats at birth. The second is linked to RTI, the rat major histocompatibility complex (MHC)