T CELL RECOGNITION & REPERTOIRE--AUTOIMMUNE THYROIDITIS

总体目标是利用小鼠实验性自身免疫性甲状腺炎 (EAT)作为探讨其致病机理的模型 导致桥本甲状腺炎（HT）中的甲状腺病变。 早期 发现H-2与甲状腺损伤有关， MHC与HT和其他自身免疫性疾病的关系。 近年来， 人类T细胞研究的观察结果与 鼠标 这些包括致敏T细胞的增殖， 同源和异源甲状腺球蛋白（Tg）及其亚群组成 以及对甲状腺靶细胞的细胞毒性。 在 小鼠，我们进一步研究了共享和独特的Tg的作用， 表位在甲状腺原性，浸润动力学 TCR α/β + T细胞亚群、免疫疗法的疗效以及 EAT中的调节机制。 我们最近的基因转移研究已经证明了EAT的易感性 H-2A分子介导的抗性和H-2 E分子介导的抗性，以及 通过针对H-2A α，β链的抗体（Ab）调节疾病- 特异性合成肽。 MHC影响之间的新关系 和T细胞亚群发病机制的研究奠定了基础， MHC/自身抗原/TCR vbeta基因使用之间的三分子相互作用 吃吧 Tg表位的自身抗原（Ag）连接可以在四个表位内。 Tg上的主要致突变位点，其在以下中高度保守： 哺乳动物物种;最近的报告显示，一个网站作为T细胞 表位 我们希望测试这些甲状腺素（T4-）的致病性- 含有EAT中的Tg表位。 假设这些保守的 表位是自身表位的主要候选者，我们建议： 1. 检测和鉴定小鼠Tg识别的促甲状腺激素表位 通过T细胞--特别强调含T4的合成肽 与人类Tg相同。 2. 检查T细胞库和TCR vbeta基因的使用， 和保守表位--重点是促甲状腺T细胞。 3. 检查MHC II类基因对TCR库的影响， 自身反应性-比较H-2A/E基因和抗体对 它们的合成肽，以及两个EAT易感基因vbeta基因缺失 单倍型。 4. 检测MHC I类基因对EAT发病机制的影响-- 关于D基因的作用和Ab对合成的 缩氨酸

The overall goal is to use murine experimental autoimmune thyroiditis (EAT) as a model to probe the recognitory and pathogenic mechanisms leading to thyroid lesions in Hashimoto's thyroiditis (HT). The early finding of H-2 linkage to thyroid damage has led to the recognition of MHC association with HT and other autoimmune diseases. In recent years, observations from human T cell studies have paralleled those found in the mouse. These include the proliferation of primed T cells to homologous and heterologous thyroglobulin (Tg), their subset composition in the thyroid, and cytotoxicity for thyroid target cells. In the mouse, we have further examined the role of shared and unique Tg epitopes in thyroiditogenicity, the infiltration kinetics of TCRalpha/beta+ T cell subsets, the efficacy of immunotherapy, as well as the regulatory mechanisms in EAT. Our recent gene transfer studies have demonstrated susceptibility to EAT mediated by H-2A molecules and resistance by H-2E molecules, as well as modulation of diseases by antibodies (Abs) to H-2A alpha,beta chain- specific synthetic peptides. The new relationship between MHC influence and T cell subset pathogenesis lays the groundwork for a study of the trimolecular interactions among MHC/self antigen/TCR vbeta gene usage in EAT. The self antigen (Ag) link of Tg epitopes may be within the four primary hormonogenic sites on Tg, which are highly conserved among mammalian species; recent report has shown one site to serve as a T cell epitope. We wish to test the pathogenicity of these thyroxine (T4-)- containing Tg epitopes in EAT. Postulating that these conserved epitopes are prime candidates for autoepitopes, we propose to: 1. Examine and identify thyroiditogenic epitopes on mouse Tg recognized by T cells--with particular emphasis on T4-containing synthetic peptides shared with human Tg. 2. Examine the T cell repertoire and TCR vbeta gene usage for shared and conserved epitopes--with emphasis on thyroiditogenic T cells. 3. Examine the MHC class II gene influence on TCR repertoire and autoreactivity--comparing the effects of H-2A/E genes and antibodies to their synthetic peptides, and vbeta gene deletion in two EAT-susceptible haplotypes. 4. Examine the MHC class I gene influence on EAT pathogenesis-- regarding the role of D genes and modulation by Abs to synthetic peptides.