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Abstract：
Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways.
摘要：
系统性硬化症（SSc）是一种多面性结缔组织疾病，其病因尚不清楚。自身免疫被认为在疾病的发展中起着关键作用，但SSc特异性自身抗体的直接致病作用仍有待确定.最近发现的针对G蛋白偶联受体（GPCRs）的功能性抗体，它们的存在已经在不同的自身免疫条件下得到证实，阐明了SSc的发病机制。这些抗体结合在免疫和非免疫细胞上表达的GPCRs作为其内源性配体，对相应的细胞内途径产生刺激或抑制作用。越来越多的证据表明,在SSc中,抗GPCRs抗体的存在与特定的临床表现相关.针对内皮素受体A型（ETAR）和血管紧张素1型受体（AT1R）的自身抗体与严重的血管病变SSc相关表现有关，虽然抗C-X-C基序趋化因子受体(CXCR)抗体似乎可预测间质性肺受累;在严重胃肠道受累患者中发现抗毒蕈碱-3乙酰胆碱受体(M3R)抗体,在硬皮病肾危象患者中检测到抗蛋白酶激活受体1(PAR1)抗体.这篇综述旨在阐明GPCR靶向自身抗体在SSc中的潜在致病意义。重点探讨其与硬皮病不同临床表现的关系。针对GPCRs的功能性自身免疫的广泛检查可能为SSc的潜在致病机制提供有价值的见解，从而能够开发针对GPCR介导的途径定制的新型治疗策略。
