Autoimmune thyroid-stimulating antibodies are activating the thyrotropin receptor (TSHR) in both the thyroid and the eye, but different molecular mechanisms are induced in both organs, leading to Graves’ disease (GD) and Graves’ orbitopathy (GO), respectively. Therapy with anti-thyroid drugs to reduce hyperthyroidism (GD) by suppressing the biosynthesis of thyroid hormones has only an indirect effect on GO, since it does not causally address pathogenic TSHR activation itself. GO is thus very difficult to treat. The activated TSHR but also the cross-interacting insulin-like growth factor 1 receptor (IGF-1R) contribute to this issue. The TSHR is a heptahelical G-protein-coupled receptor, whereas the IGF-1R is a receptor tyrosine kinase. Despite these fundamental structural differences, both receptors are phosphorylated by G-protein receptor kinases, which enables β-arrestin binding. Arrestins mediate receptor internalization and also activate the mitogen-activated protein kinase pathway. Moreover, emerging results suggest that arrestin plays a critical role in the cross-interaction of the TSHR and the IGF-1R either in their common signaling pathway and/or during an indirect or potential TSHR/IGF-1R interaction. In this review, novel pharmacological strategies with allosteric small-molecule modulators to treat GO and GD on the level of the TSHR and/or the TSHR/IGF-1R cross-interaction will be discussed. Moreover, monoclonal antibody approaches targeting the TSHR or the IGF-1R and thereby preventing activation of either receptor will be presented. Another chapter addresses the immunomodulation to treat GO using TSHR-derived peptides targeting the human leukocyte antigen DR isotope (HLA-DR), which is a feasible approach to tackle GO, since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients.
Eur Thyroid J

中文翻译：

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调节TSH受体信号传导的治疗功效

自身免疫刺激甲状腺的抗体正在激活甲状腺和眼中的促甲状腺激素受体（TSHR），但是在两个器官中诱导出不同的分子机制，分别导致了Graves病（GD）和Graves眼眶病（GO）。通过抑制甲状腺激素的生物合成来减少甲状腺功能亢进症（GD）的抗甲状腺药物疗法仅对GO产生间接作用，因为它并没有因果关系解决TSHR活化本身。因此，GO很难治疗。激活的TSHR以及交叉相互作用的胰岛素样生长因子1受体（IGF-1R）都导致了此问题。TSHR是七螺旋G蛋白偶联受体，而IGF-1R是酪氨酸激酶受体。尽管存在这些基本的结构差异，但两种受体均被G蛋白受体激酶磷酸化，它可以使β-arrestin结合。Arrestins介导受体内在化并激活有丝分裂原激活的蛋白激酶途径。此外，新出现的结果表明，抑制素在它们共同的信号传导途径中和/或间接或潜在的TSHR / IGF-1R相互作用中，在TSHR和IGF-1R的交叉相互作用中起关键作用。在这篇综述中，将讨论用变构小分子调节剂治疗TSHR和/或TSHR / IGF-1R交叉相互作用水平的GO和GD的新药理策略。此外，将提出靶向TSHR或IGF-1R并由此防止任一受体活化的单克隆抗体方法。另一章介绍了使用针对人类白细胞抗原DR同位素（HLA-DR）的TSHR衍生肽治疗GO的免疫调节，
甲状腺素