Elia Giusy, Fallahi Poupak, Ragusa Francesca, Paparo Sabrina Rosaria, Mazzi Valeria, Benvenga Salvatore, Antonelli Alessandro, Ferrari Silvia Martina
Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Front Pharmacol. 2021 Oct 28;12:754386. doi: 10.3389/fphar.2021.754386. eCollection 2021.
Graves' disease (GD) is a condition caused by an autoimmune process involving the thyroid gland, whose main outcome is hyperthyroidism. TSAb start the autoimmune process stimulating the overproduction of thyroid hormones. In addition, TSAb can stimulate TSH-R expressed in fibroblasts and orbital pre-adipocytes leading to the manifestation of Graves' ophtalmopathy (GO). Also, autoantibodies directed against IGF-1R have an important role in immune-pathogenesis of GO. Fundamental is the role played by cytokines (IFN-γ, TNF-α, Il-6), and Th1 chemokines in the immune-pathogenesis of both disorders, particularly in the active phase. Novel discoveries in the field led to the investigation of promising therapies, such as immune-therapies towards specific antigens (for example against TSH-R), aiming in restoring the immune tolerance versus the immune dominant epitopes associated with autoimmunity in GD. Moreover, Etanercept (that blocks the TNF-mediated inflammatory responses), TCZ (that acts against the IL-6 receptor), and RTX (that acts against CD20) have proven to be useful and safe therapeutic options in refractory GO treatment. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody), have been revealed effective in the treatment of patients with moderate-severe GO and it is now approved for GO therapy in United States. Molecules able to act as antagonists of CXCR3, or to block CXCL10, are also under study. More extensive researches are needed to deepen out these drugs as well as to identify new targeted and effective therapies, that will permit a more precise identification of GD, or GO, patients able to respond to specific targeted therapies.
格雷夫斯病（GD）是一种由涉及甲状腺的自身免疫过程引起的疾病，其主要结果是甲状腺功能亢进。促甲状腺素受体抗体（TSAb）启动自身免疫过程，刺激甲状腺激素过度产生。此外，TSAb可刺激成纤维细胞和眼眶前脂肪细胞中表达的促甲状腺素受体（TSH-R），导致格雷夫斯眼病（GO）的表现。此外，针对胰岛素样生长因子-1受体（IGF-1R）的自身抗体在GO的免疫发病机制中起重要作用。细胞因子（干扰素-γ、肿瘤坏死因子-α、白细胞介素-6）和Th1趋化因子在这两种疾病的免疫发病机制中，尤其是在活动期，所起的作用至关重要。该领域的新发现促使人们对有前景的疗法进行研究，例如针对特定抗原的免疫疗法（例如针对TSH-R），旨在恢复对与GD自身免疫相关的免疫显性表位的免疫耐受。此外，依那西普（可阻断肿瘤坏死因子介导的炎症反应）、托珠单抗（可作用于白细胞介素-6受体）和利妥昔单抗（可作用于CD20）已被证明是难治性GO治疗中有用且安全的治疗选择。此外，替普罗单抗（一种人源单克隆抗IGF-1R阻断抗体）已被证明对中度至重度GO患者有效，目前已在美国获批用于GO治疗。能够作为CXCR3拮抗剂或阻断CXCL10的分子也在研究中。需要更广泛的研究来深入了解这些药物，并确定新的靶向有效疗法，这将有助于更精确地识别能够对特定靶向疗法产生反应的GD或GO患者。
