SPONTANEOUS POLYENDOCRINE AUTOIMMUNE DISEASE

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Type I (insulin-dependent) diabetes mellitus is often associated with autoimmune diseases like Graves' disease, Hashimoto's thyroiditis, Addison's disease and simply autoantibodies without clinical manifestation. The NOD mouse develops autoimmune type I diabetes secondary to islet beta cell destruction by infiltrating immune cells (insulitis). The incidence of diabetes is 90% in females and 50% in males in our Joslin colony. The incidence of insulitis is 100% in female and male NOD mice at 10 weeks of age. There is a difference in the severity of insulitis between female and male NOD mice. In addition to type I diabetes, the NOD mouse develops autoimmune thyroiditis at 18% incidence and adrenalitis at 7% incidence in our colony. In contrast to the insulitis lesion, the tissue damage by the infiltrating immune cells was weak (grade 1) in the thyroid and adrenal glands from NOD mice. In our breeding studies of NOD with Mus spretus, a wild mouse strain, we have found two different types of diabetes, pretype I and type II (non-insulin-dependent) diabetes, and a higher incidence of thyroiditis (47% in BC1 females and 33% in BC1 males) and adrenalitis (83% in BC1 females and 54% in BC1 males) with more severe damages by infiltrating immune cells. This animal model of BC1[(NODxMus spretus)F1xNOD] represent a unique opportunity to study the interdependency between autoimmune diabetes, thyroiditis and adrenalitis. Our preliminary studies indicate that thyroiditis is possibly linked to D5Mit 59 locus on chromosome 5, adrenalitis to D7Mit 40 locus on chromosome 7, and type II diabetes to D1Mit 17 and D1Mit16 on chromosome 1 and D15Mit 6 on chromosome 15. Our proposed studies aim to characterize type I and type II diabetes, thyroiditis and adrenalitis in the backcross animals and study the genetic susceptibility to the autoimmune endocrine diseases in the following ways: a) Establishment of 100 more diabetic BC1[(NODxMus spretus)F1xNOD] animals. b) Histological examination of the pancreas, thyroid and adrenal glands of the diabetic and nondiabetic BC1[(NODxMus spretus)F1xNOD] animals. c) Linkage analysis of SSR (simple sequence repeat) markers with insulitis, thyroiditis, adrenalitis, insulin-resistance and type II diabetes in BC1[(NODxMus spretus)F1xNOD], Bc2(BC1xNOD) and BC3(BC2xNOD).