The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim.
The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim.
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DOI：
10.1172/jci17069
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发表时间：
2003-06
期刊：
影响因子：
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通讯作者：
Chun‐Rong Chen;P. Pichurin;Y. Nagayama;F. Latrofa;B. Rapoport;S. McLachlan
中科院分区：
文献类型：
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作者：
Chun‐Rong Chen;P. Pichurin;Y. Nagayama;F. Latrofa;B. Rapoport;S. McLachlan
Graves病是一种常见的影响人类器官特异性自身免疫性疾病，与所有其他自身免疫性疾病不同的是，它与靶器官功能亢进有关，而不是器官损害。临床甲状腺毒症是由激活促甲状腺素受体（TSHR）的自身抗体直接引起的。Graves病的病因是多因素的，其中非遗传因素起重要作用。对于后者，有一种有趣的可能性，即靶抗原的分子结构有助于甲状腺刺激自身抗体（TSAb’s）的发展。在糖蛋白激素受体中，只有TSHR在分子内分裂为二硫连接亚基，并随之脱落一些细胞外自身抗体结合的A亚基。功能性自身抗体不会产生于非切割性糖蛋白激素受体。最近，TSAb被发现优先识别脱落而不是附着的A亚基。在这里，我们使用一种新的腺病毒介导的Graves病动物模型来表明，当腺病毒表达游离a亚基时，甲状腺肿和甲状腺功能亢进的发生程度要大得多，而不是基因修饰的TSHR，其分裂成亚基。这些数据表明，shed A亚基诱导或放大导致甲亢的免疫反应，并为Graves病的病因学提供了新的见解。
Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role. Of the latter, there is the intriguing possibility that the molecular structure of the target antigen contributes to the development of thyroid-stimulatory autoantibodies (TSAb's). Among the glycoprotein hormone receptors, only the TSHR undergoes intramolecular cleavage into disulfide-linked subunits with consequent shedding of some of the extracellular, autoantibody-binding A subunits. Functional autoantibodies do not arise to the noncleaving glycoprotein hormone receptors. Recently, TSAb's were found to preferentially recognize shed, rather than attached, A subunits. Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits. These data show that shed A subunits induce or amplify the immune response leading to hyperthyroidism and provide new insight into the etiology of Graves disease.