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)作为探索识别和致病机制的模型 导致桥本甲状腺炎(HT)的甲状腺损害。最早的 H-2与甲状腺损害的联系的发现使人们认识到 MHC与高血压和其他自身免疫性疾病的关系。近年来， 来自人类T细胞研究的观察结果与在 那只老鼠。这些包括预置的T细胞增殖到 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作用。在 鼠标，我们进一步研究了共享和唯一TG的作用 促甲状腺激素活性表位的渗透动力学 TCRα/β+T细胞亚群、免疫治疗的疗效以及 EAT中的调节机制。 我们最近的基因转移研究已经证明了对食物的易感性 由H-2a分子和H-2e分子介导的抗性，以及 H-2Aα、β链抗体对疾病的调节作用 特定的合成肽。MHC影响之间的新关系 并为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。TG表位的自身抗原(Ag)连接可能在四个 甘油三酯上的主要激素产生部位，在 哺乳动物物种；最近的报告显示有一个部位充当T细胞 表位。我们希望测试这些甲状腺激素(T4-)的致病性- 在EAT中含有TG表位。假设这些守恒 表位是自动表位的主要候选者，我们建议： 1.检测和鉴定小鼠甘油三酯识别的促甲状腺激素表位 通过T细胞--特别是含有T4的合成肽 与人类TG共享。 2.检查共享的T细胞谱系和TCR vbeta基因使用情况 和保守的表位--重点是促甲状腺T细胞。 3.检测MHC-II类基因对TCR谱带的影响 自身反应性--比较H-2A/E基因和抗体对 它们的合成肽和vbeta基因在两个EAT易感人群中的缺失 单倍型。 4.检测MHC-I类基因对EAT发病的影响-- D基因的作用及单抗对合成的调控 多肽。

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.