T CELL RECOGNITION--REPERTOIRE IN 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)甲状腺功能减退的甲状腺损害 综合症。这次续签申请的一个主要推动力是强调 使用人类白细胞抗原II类转基因小鼠和人甲状腺抗原是因为 的新发现在过去两年达到顶峰。新的发现 包括：1)人类白细胞抗原-DR3转基因使人对抗食性AS易感 以及II类缺陷小鼠，允许任何一种EAT诱导 甲状腺球蛋白(HTG)或小鼠(M)TG。2)类似于H_2A多态 决定EAT易感性的是，HLA-DRB1基因多态性是一个决定因素， 由于人类白细胞抗原DR2转基因小鼠对MTG诱导的EAT具有抵抗力。3) 初步数据显示，也可以表现出人类白细胞抗原-DQ多态， 对HTG或MTG有不同的响应，暗示HTG独特，以及 MTG-独特的，与每个物种相关的表位。4)身份识别 某些保守的、含促甲状腺激素(T4)的多肽， 它们不依赖于Tg上的可变碘残留量 免疫原性，现在可以结合独特的表位进行研究。 我们建议： 1.确定人类白细胞抗原II类基因在自身免疫性甲状腺炎中的作用 检测人类白细胞抗原DRB1和人类白细胞抗原DQ基因多态性--潜在的人类白细胞抗原关联 带着超音速。 2.确定人类白细胞抗原-DR和人类白细胞抗原-DQ基因在双胎中的相互影响 转基因小鼠对EAT的敏感性和抵抗力--重点是 基因互补和下调(保护)。 3.确定MTG和HTG特有的促甲状腺激素表位--检测T细胞 细胞库和功能。 4.确定人类白细胞抗原与甘油三酯的相关性是否与其他主要疾病相关 甲状腺抗原-使用重组甲状腺过氧化物酶(RTPO)和甲状腺- 刺激素受体(RTSHR)。

The overall goal is to use murine experimental autoimmune thyroiditis (eat) as a model to probe the recognitory and pathogenic mechanisms leading to thyroid damage in Hashimoto's thyroititis (HT), the hypothyroid syndrome. A major thrust in this renewal application is the emphasis on the use of HLA class II transgenic mice and human thyroid antigens because of new findings culminated with the last 2 years. The new findings include: 1) HLA-DR3 transgene confers susceptibility to EAT-resistant, as well as class II-deficient mice, permitting EAT induction by either thyroglobulin (HTg) or mouse (M) Tg. 2) Similar to H2A polymorphism determining EAT susceptibility, HLA-DRB1 polymorphism is a determinant, since HLA-DR2 transgenic mice are resistant to MTg-induced EAT. 3) Preliminary data show that HLA-DQ polymorphism can also be demonstrated, with distinct responses to HTg or MTg, implicating HTg-unique, as well as MTg-unique, epitopes associated with each species. 4) The identification of certain conserved, thyroiditogenic thyroxine (T4)-containing peptides, which are not dependent on the variable iodine residues on Tg for immunogenicity, can now be studied in conjunction with unique epitopes. We propose to: 1. Determine the role of HLA class II genes in autoimmune thyroiditis by examining HLA-DRB1 and HLA-DQ polymorphism--potential for HLA association with HT. 2. Determine the mutual influence of HLA-DR and HLA-DQ genes in double transgenic mice on EAT susceptibility and resistance--with emphasis on gene complementation and down-regulation (protection). 3. Identify thyroiditogenic epitopes unique to MTg and HTg--examining T cell repertoire and function. 4. Determine if HLA association with Tg correlates with other major thyroid antigens--using recombinant thyroperoxidase (rTPO) and thyroid- stimulating hormone receptor (rTSHR).