SPONTANEOUS POLYENDOCRINE AUTOIMMUNE DISEASE

I型（胰岛素依赖型）糖尿病通常与以下疾病相关： 自身免疫性疾病，如格雷夫斯病，桥本甲状腺炎， 阿狄森氏病和单纯的自身抗体没有临床意义 表现。NOD小鼠发生继发性自身免疫性I型糖尿病 胰岛β细胞被浸润的免疫细胞破坏（胰岛炎）。 我们乔斯林的糖尿病发病率女性为90%，男性为50 殖民地胰岛炎的发病率在雌性和雄性NOD小鼠中为100%， 10周大。胰岛炎的严重程度是有区别的 雌性和雄性NOD小鼠之间。除了I型糖尿病，NOD 小鼠发生自身免疫性甲状腺炎的发生率为18%， 7%的发病率。与胰岛炎病变相反， 浸润性免疫细胞的组织损伤较弱（1级）， 甲状腺和肾上腺。在我们对NOD的育种研究中， 用一种野生小鼠品系Mus spretus，我们发现了两种不同的类型， 糖尿病、I型和II型（非胰岛素依赖型）糖尿病，以及 甲状腺炎的发病率较高（BC1女性为47%，BC1女性为33%）， 男性）和肾上腺素（BC1女性为83%，BC1男性为54%）， 免疫细胞浸润造成的严重损害。这个动物模型 BC1[（NODxMus spretus）F1xNOD]代表了研究 自身免疫性糖尿病、甲状腺炎和肾上腺素之间的相互依赖性。 我们的初步研究表明甲状腺炎可能与 5号染色体上的D5Mit 59位点，肾上腺素对5号染色体上的D7Mit 40位点， 7号染色体，II型糖尿病与染色体上的D1Mit 17和D1Mit 16有关 1和D15Mit 6。 我们提议的研究旨在描述I型和II型糖尿病的特征， 甲状腺炎和肾上腺素的回交动物和研究遗传 自身免疫性内分泌疾病的易感性表现在以下几个方面： a）建立100个以上的糖尿病BC1[（NODxMus spretus）F1xNOD] 动物 B）胰腺、甲状腺和肾上腺的组织学检查 糖尿病和非糖尿病BC1[（NODxMus spretus）F1xNOD]动物。 c）SSR（简单序列重复）标记与 胰岛炎、甲状腺炎、肾上腺素、胰岛素抵抗和II型 BC1[（NODxMus spretus）F1xNOD]、BC2（BC1xNOD）和BC3（BC2xNOD）中的糖尿病。

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).