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

自身免疫性TSH受体疾病的概念、发病机制和自身免疫机制。

基本信息

批准号：
06454338
负责人：
MORI Toru
金额：
$ 4.16万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06454338/
关键词：
TSH receptor autoimmune disease Graves'disease HLA immunoglobulin gene TSH receptor antibody epitope autoimmune TSH receptor disease エピトープ分析甲状腺機能低下症自己免疫 MHCクラスII抗原自己免疫性甲状腺疾患 HLA-DP Tリンパ球受容体

项目摘要

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

我们对自身免疫性TSH受体疾病的概念、发病机制和自身免疫机制进行了研究。自身免疫性TSH受体疾病的新概念先前我们报道了Graves病和桥本甲状腺炎之间HLA-DPw2频率的高度显著差异。在这项研究中，我们发现由阻断受体抗体引起的甲状腺功能减退与Graves病有遗传相似性，而与特发性黏液性水肿没有遗传相似性。此外，HLA-DP抗原在Graves患者的甲状腺上皮细胞上表达强烈且异常。基于这些结果，我们提出了一种新的自身免疫性TSH受体疾病的概念，这种疾病在遗传上和自身抗体产生机制上与桥本或特发性黏液性水肿不同。发病机制观察到TSH受体的t细胞和b细胞表位存在一定的异质性。然而，我们证明了TSH受体特异性区域（Aa No.355附近）对受体抗体产物的主要重要性。通过转染研究，我们发现该区域的缺失突变体cDNA可以诱导组成性激活，进而，我们可以通过免疫该区域对应的合成肽来产生刺激性和阻断性的单克隆受体抗体。受体抗体免疫球蛋白基因分析通过对患者外周血的b细胞克隆，我们证实Graves血清中的TSAb和TBII是不同b细胞的产物，甲状腺功能减退患者血清中的TBII均与TSBAb相关。我们进一步对免疫球蛋白基因进行了详细的分析，并对转染小鼠骨髓瘤细胞系获得的VH和VK进行了重建。因此，我们能够在体外产生一种推荐的TSAb。结论自身免疫性TSH受体疾病与HLA-DP相关，HLA-DP可通过在甲状腺细胞上的异常强表达激活特异性T细胞。此外，TSH受体抗体产生的最初步骤被认为起源于Aa No.355周围TSH受体特异性区域的致敏。这表明，随后的决定性扩散将诱导产生生物活性受体抗体，如TSAb和TSBAb。少