促甲状腺素受体抗体在胫前粘液性水肿发病中的作用研究

Pretibial myxedema (PTM) is a refractory skin disease often associated with Graves' hyperthyroidism (GD). Its pathogenesis is rarely studied and there is a lack of satisfactory clinical treatment. In recent years, our group found that the trimodality therapy for PTM, namely "glucocorticoid injection, parcel, high-power UVA1", with high efficiency, low recurrence rate, no obvious side effects. The pathogenic antibody of GD is the thyrotrophin receptor antibody (TRAb), which also has higher titers in the peripheral blood of PTM patients. In addition, it has been reported that TSHR is expressed on the surface of human fibroblasts and specifically binds to the pathogenic autoantibody TRAb. Therefore, we propose the following hypothesis: TRAb, in combination with TSHR on the surface of fibroblasts, activates the adenylate cyclase-cAMP pathway at the local lesion site, inducing the secretion of cytokines, infiltrating T lymphocytes and promoting fibroblasts proliferation, excessive synthesis of hyaluronic acid, resulting in mucin deposition and collagen proliferation. In this study, we will study the expression of TRAb and TSHR, the local T, B cell phenotype and local immune microenvironment in PTM patients and the pathological mechanism of fibroblasts. This study, for the first time, systematically explores the pathogenesis of PTM and provides experimental evidence for the "localized treatment of skin PTM".

胫前粘液性水肿（PTM）是一种伴发于Graves甲亢（GD）的难治性皮肤病，其发病机制鲜有研究，临床缺乏有效的治疗手段。近年来，本课题组发现针对皮损的“糖皮质激素局部注射、封包、大功率UVA1照射三联疗法”有效率高，副作用小。GD的致病性抗体为促甲状腺素受体抗体（TRAb），在PTM外周血中高表达。且有研究表明人成纤维细胞表达促甲状腺素受体（TSHR），可与TRAb特异性结合。因此，我们提出以下假说：皮损局部TRAb与成纤维细胞表面TSHR结合，激活腺苷酸环化酶-cAMP通路，引起细胞因子分泌、淋巴细胞浸润，促使成纤维细胞增殖，合成过多透明质酸，导致粘蛋白沉积和胶原增生。本研究中，课题组将对PTM患者皮损局部TRAb和TSHR表达情况，T、B细胞的表型和局部免疫微环境以及成纤维细胞的病理效应机制进行研究。该研究首次系统探究PTM的发病机制，并为临床针对皮损的“三联疗法”提供实验依据。

胫前粘液性水肿（PTM）是一种伴发于Graves甲亢（GD）的难治性皮肤病，尽管促甲状腺素受体抗体受体抗体（TRAb）、细胞因子和生长因子刺激的成纤维细胞可能参与发病，但是具体的发病机制鲜有研究，缺乏有效临床治疗手段。近年来，本课题组发现针对皮损的“三联疗法”：糖皮质激素局部注射、封包、大功率UVA1的治疗有效，患者缓解期长，且不易复发。课题组假设皮肤局部免疫微环境，包括抗原和抗体、T细胞、B细胞、浆细胞和成纤维细胞，可能在PTM的发展中起重要作用。PTM患者的研究结果表明，血液中促甲状腺激素受体抗体（TRAb）的增加与皮损的真皮厚度呈正相关。进一步分析显示，皮损中有较多的CD3+T细胞和CD20+B细胞。这些T细胞和B细胞紧密接触，表明该区域可能形成诱导性皮肤相关淋巴组织（iSALT）。此外，我们发现浸润的浆细胞可以分泌TRAb，证明皮肤中除甲状腺外的B细胞是TSHR抗体的额外来源。同时，患者皮肤或皮肤匀浆中的T细胞和B细胞可促进胫前成纤维细胞的增殖。总之，我们的研究结果表明皮肤的局部免疫微环境可能在PTM的发展中起重要作用。我们对这些免疫细胞在PTM中的功能以及病灶区皮肤免疫微环境的解析将有利于PTM病人新治疗靶点的发现。