RECOGNITORY AND PATHOGENIC MECHANISMS IN AUTOIMMUNITY

小鼠实验性自身免疫性甲状腺炎（EAT）可作为 慢性淋巴细胞性甲状腺炎（桥本病）的研究，以及 其他器官特异性自身免疫性疾病。 这个项目的总体目标是 本课题是利用小鼠EAT来探讨小鼠EAT的免疫和致病性， 导致甲状腺功能障碍的机制。 在人类中，自身免疫系统 反应受基因控制。 一种主要的甲状腺抗原 甲状腺球蛋白（Tg），可用于诱导EAT的遗传 易感菌株，与主要组织相容性复合体（MHC）相连。 其免疫机制受MHC Ⅰ-A亚区控制， 致病机制受到其他修饰基因的影响，如D MHC的终结 我们已经观察到，人类之间的共同决定因素 小鼠Tg能激活免疫小鼠的T淋巴细胞， 体内甲状腺炎症并在体外产生细胞毒性T细胞。 我们 目的是：1）增殖识别小鼠Tg特异性或 通过克隆以及通过融合形成T细胞杂交瘤来共享表位; 2)进一步表征T细胞系及其后代， I-亚区限制性和表位特异性; 3）确定 T细胞系（和克隆）引起疾病的功能能力， 体内和体外细胞毒性的研究，以及D-末端基因的影响; 4） 检查T细胞亚群浸润甲状腺的动力学及其 在免疫动物中的原位分布;和5）分析和比较 体外活化细胞系的甲状腺浸润动力学 那些完整的动物。

Experimental autoimmune thyroiditis (EAT) in mice serves as a prototype for the study of chronic lymphocytic thyroiditis (Hashimoto's disease), as well as other organ-specific autoimmune disorders. The overall goal of this project is to use murine EAT to probe the recognitory and pathogenic mechanisms leading to thyroid dysfunction. As in the human, the autoimmune response is under genetic control. A major thyroid antigen is thyroglobulin (Tg) which can be used to induce EAT in genetically susceptible strains, linked to the major histocompatibility complex (MHC). The recognitory mechanism is under MHC I-A subregion control, but pathogenic mechanisms are influenced by other modifying genes such as the D end of the MHC. We have observed that shared determinants between human and mouse Tg can activate the T lymphocytes of immunized mice to produce thyroid inflammation in vivo and generate cytotoxic T cells in vitro. Our aims are to: 1) propagate T cell subsets recognizing mouse Tg-specific or shared epitopes by cloning, as well as by fusion to form T cell hybridomas; 2) characterize the T cell lines and their progenies further as to I-subregion restriction and epitope specificity; 3) determine the functional capacities of the T cell lines (and clones) to cause disease in vivo and develop cytotoxicity in vitro, and the effect of D-end genes; 4) examine the kinetics of T cell subsets infiltrating the thyroid and their in situ distribution in immunized animals; and 5) analyze and compare the kinetics of thyroid infiltration of in vitro activated cell lines with those of intact animals.