Concept, pathogenesis and autoimmune mechanisms of autoimmune TSH receptor disease.

我们对自身免疫性TSH受体病的概念、发病机制和自身免疫机制进行了研究。1.自身免疫性TSH受体病的新概念以前我们曾报道过在Graves病和桥本甲状腺炎之间存在非常显著的差异。在这项研究中，我们发现甲状腺功能减退症的遗传相似性是由于Graves病的受体抗体阻断而不是特发性粘液水肿。此外，在Graves病患者的甲状腺上皮细胞上也有强烈和异常的HLA-DP抗原表达。根据这些结果，我们提出了自身免疫性TSH受体病的新概念，它在基因上和自身抗体产生机制上都不同于桥本或特发性粘液性水肿病。2.发病机制观察到TSH受体上T细胞和B细胞表位存在一定的异质性。然而，我们证明了促甲状腺激素受体特异性区域(约AA355)在受体抗体产物…上的主要重要性。更多的离子。3.受体抗体免疫球蛋白基因的分析通过从患者外周血中克隆B细胞，我们发现Graves患者血清中的TSAb和TbII是不同B细胞的产物，甲减患者血清中的TSAb和TbII均与TSBAb有关。我们进一步对免疫球蛋白基因进行了详细的分析，并将其导入小鼠骨髓瘤细胞系，构建了VH和VK基因。结论自身免疫性TSH受体病与HLADP密切相关，HLADP可能通过在甲状腺细胞上的异常强表达而激活特异性T细胞。此外，TSH受体抗体产生的最初步骤被认为起源于AA355附近的TSH受体特异性区域的敏化。建议紧随其后的是决定簇扩散，这将诱导产生生物活性受体抗体，如TSAb和TSBAb。较少

We studied the concept, pathogenesis and autoimmune mechanisms of autoimmune TSH receptor disease.1.A new concept of autoimmune TSH receptor diseasePreviously we have reported a highly significant difference in the HLA-DPw2 frequencies between Graves'disease and Hashimoto thyroiditis. In this study, we found genetic similarity of hypothyroidism due to blockig receptor antibody to Graves'disease but not to idiopathic myxedema. Further, strong and aberrant expressions of HLA-DP antigen on the thyroid epithelial cells of Graves'patients were also indicated. From these results, we proposed a new concept of autoimmune TSH receptor disease which is different from Hashimoto or idiopathic myxedema genetically and in the autoantibody producing mechanisms.2.PathogenesisPresence of certain heterogeneity in the T-and B-cell epitopes on the TSH receptor was observed. However, we demonstrated the primary importance of a TSH receptor specific region (around Aa No.355) on the receptor antibody product … More ion. A deletion mutant cDNA of the region was known to induce constitutive activation by transfection study, and further, we could produce stimulatory and blocking monoclonal receptor antibodies by immunizing a synthetic peptide corresponding to the region.3.Analysis of immunoglobulin gene of the receptor antibodiesThrough B-cell cloning from peripheral blood of the patients, we demonstrated that TSAb and TBII in Graves'sera are the products of different B-cells and that all TBII in hypothyroid patients sera are associated with TSBAb. We further analyzed immunoglobulin genes in details and performed to reconstitute VH and VK such obtained by transfection into mouse myeloma cell line. Thus, we were able to produce a recominant TSAb, in vitro.4.ConclusionAutoimmune TSH receptor disease was indicated to relate significantly with HLA-DP which may activate specific T cells via aberrant and strong expressions on the thyroid cells. Further, the initial step of the TSH receptor antibody production was considered to be originated from the sensitization of the TSH receptor specific region around Aa No.355. This was suggested to be followed by determinant spreading which would induce the productions of bioactive receptor antibodies such as TSAb and TSBAb. Less