Study on mechanisms of induction of anti-thyrotropin receptor antibodies in murine experimental Graves'disease.

为了探讨抗促甲状腺激素受体抗体在Graves病中的诱导机制，我们建立了一种新的小鼠模型，以转染人促甲状腺激素受体基因的成纤维细胞为免疫原，呈现与人Graves病相似的抗促甲状腺激素受体介导的促甲状腺功能亢进。研究表明，促甲状腺激素受体抗体的产生完全依赖于促甲状腺激素受体表达的成纤维细胞中MHC类分子的表达，尽管促甲状腺激素受体抗体的总水平受MHC以外的一些基因的影响。这些结果强烈提示II类MHC分子在靶器官（在这种情况下，甲状腺滤泡细胞）上的异常表达对于自身免疫的发生或进展非常重要。通过转染人促甲状腺激素受体和大鼠促黄体激素/绒毛膜促性腺激素受体嵌合体受体的成纤维细胞，我们进一步证明了促甲状腺激素的n端部分在诱导抗促甲状腺激素受体中起关键作用。最后，我们将CD86基因导入小鼠成纤维细胞，并用促甲状腺素受体阳性成纤维细胞免疫小鼠，促甲状腺素受体阳性成纤维细胞对T细胞具有更高的共刺激能力。结果表明，CD86对抗促甲状腺激素受体抗体的诱导无加性作用。

In order to investigate the mechanisms of induction of anti-thyrotropin receptor antibodies in Graves' disease, we established a new mouse model presenting stimulating anti-thyrotropin receptor-mediated hyperthyroidism with similar features of Graves' disease in human in which fibroblasts transfected with human thyrotropin receptor gene as an immunogen, The study showed that stimulating anti- thyrotropin receptor antibodies is exclusively dependent on the expression of class IT MHC molecule on the thyrotropin receptor-expressing fibroblasts used for immunization although total level of anti- thyrotropin receptor antibodies is influenced by some gene(s) other than MHC.These results strongly suggest that aberrant expression of class II MHC molecule on target organ (in this case, thyroid follicular cells) is quite important for initiation or progression of autoimmunity. By use of fibroblasts transfected with chimera receptors between human thyrotropin receptor and rat lutenizing hormone/chorionic gonadotropin receptor, we further demonstrated that N-terminal portion of the thyrotropin is crucial in induction of anti-thyrotropin receptor. Finally, we introduced CD86 gene into murine fibroblasts and immunized mice with thyrotropin receptor-positive fibroblasts which as higher costimulatory capacity for T cells. The results indicated in this system that CD86 has no additive effect on induction of anti-thyrotropin receptor antibodies.