RECOGNITORY AND PATHOGENIC MECHANISMS IN AUTOIMMUNITY

以小鼠实验性自身免疫性甲状腺炎(EAT)为原型 慢性淋巴细胞性甲状腺炎(桥本氏病)的研究 和其他器官特异性自身免疫性疾病一样。这个项目的总体目标是 项目是利用小鼠的EAT来探索识别和致病 导致甲状腺功能障碍的机制。就像人类一样，自体免疫 反应受基因控制。一种主要的甲状腺抗原是 甲状腺球蛋白(TG)在遗传上可用于诱导EAT 与主要组织相容性复合体(MHC)相关联的敏感菌株。 识别机制受MHC I-A亚区控制，但 致病机制受其他修饰基因的影响，如D MHC的末尾。我们观察到人类之间的共同决定因素 小鼠甘油三酯能激活免疫小鼠的T淋巴细胞产生 体内甲状腺炎症和体外产生细胞毒性T细胞。我们的 目的是：1)繁殖T细胞亚群，识别小鼠TG特异性或 通过克隆共享表位，以及通过融合形成T细胞杂交瘤； 2)进一步鉴定T细胞系及其后代，以 I-亚区限制和表位特异性；3)决定 T细胞系(和克隆)致病的功能能力 体内和体外发展的细胞毒作用，以及D-端基因的影响；4) 检测T细胞亚群渗入甲状腺的动力学及其临床意义 在免疫动物体内的原位分布；5)分析和比较 促甲状腺激素体外激活细胞系的甲状腺渗透动力学 那些完好无损的动物。

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.