Rapoport Basil, McLachlan Sandra M
Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA, USA.
Horm Metab Res. 2018 Dec;50(12):840-852. doi: 10.1055/a-0725-9297. Epub 2018 Oct 24.
After investigating thyroid autoimmunity for more than 40 years, we present a personal perspective on the field. Despite effective therapies for Graves' hyperthyroidism and Hashimoto's thyroiditis, cures are elusive. Novel forms of therapy are being developed, such as small molecule inhibitors of the TSH receptor (TSHR), but cure will require immunotherapy. This goal requires advances in understanding the pathogenesis of thyroid autoimmunity, the 'keys' for which are the thyroid antigens themselves. Presently, however, greater investigative focus is on non-thyroid specific immune cell types and molecules. Thyroid autoantigens are the drivers of the autoimmune response, a prime example being the TSHR. In our view, the TSHR is the culprit as well as the victim in Graves' disease because of its unique structure. Unlike the closely related gonadotropin receptors, the TSHR cleaves into subunits and there is strong evidence that its shed extracellular A-subunit, not the holoreceptor, is the major antigen driving pathogenic thyroid stimulating autoantibodies (TSAb) development. There is no Graves' disease of the gonads. Studies of potential antigen-specific immunotherapies require an animal model. Such models have been developed in which TSAb can be induced or, more importantly, arise spontaneously. Not appreciated until recently by thyroid investigators is that B cell surface autoantibodies are highly efficient 'antigen receptors' and the epitope to which an autoantibody binds influences antigen processing and which peptide is presented to T cells. These animal models and recombinant human autoantibodies cloned from Graves' and Hashimoto's B cells (plasma cells) are available for study by future generations.
在对甲状腺自身免疫进行了40多年的研究之后，我们在此呈现对该领域的个人观点。尽管针对格雷夫斯病（Graves' hyperthyroidism）和桥本甲状腺炎（Hashimoto's thyroiditis）有有效的治疗方法，但治愈仍然难以实现。新的治疗形式正在研发中，例如促甲状腺激素受体（TSH receptor, TSHR）的小分子抑制剂，但治愈需要免疫疗法。这一目标需要在理解甲状腺自身免疫发病机制方面取得进展，而“关键”在于甲状腺抗原本身。然而目前，更多的研究焦点集中在非甲状腺特异性免疫细胞类型和分子上。甲状腺自身抗原是自身免疫反应的驱动因素，促甲状腺激素受体就是一个主要例子。在我们看来，促甲状腺激素受体在格雷夫斯病中既是罪魁祸首也是受害者，因为其独特的结构。与密切相关的促性腺激素受体不同，促甲状腺激素受体会裂解成亚基，并且有强有力的证据表明，其脱落的细胞外A亚基而非完整受体，是驱动致病性促甲状腺素自身抗体（TSAb）产生的主要抗原。性腺不会发生格雷夫斯病。对潜在抗原特异性免疫疗法的研究需要动物模型。已经开发出了这样的模型，在其中可以诱导产生TSAb，或者更重要的是，TSAb可以自发产生。直到最近甲状腺研究人员才认识到，B细胞表面自身抗体是高效的“抗原受体”，自身抗体结合的表位会影响抗原加工以及呈递给T细胞的肽段。这些动物模型以及从格雷夫斯病和桥本甲状腺炎的B细胞（浆细胞）克隆的重组人自身抗体可供后代研究使用。
