Riemekasten Gabriela, Distler Jörg H W
Clinic for Rheumatology and Clinical Immunology, University Clinic Schleswig-Holstein and University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Ther Adv Musculoskelet Dis. 2022 Aug 9;14:1759720X221109404. doi: 10.1177/1759720X221109404. eCollection 2022.
Systemic sclerosis (SSc) is a systemic autoimmune disease with the key features of inflammation, vasculopathy and fibrosis. This article focussed on emerging fields based on the authors' current work and expertise. The authors provide a hierarchical structure into the studies of the pathogenesis of SSc starting with the contribution of environmental factors. Regulatory autoantibodies (abs) are discussed, which are parts of the human physiology and are specifically dysregulated in SSc. Abs against the angiotensin II receptor subtype 1 (AT1R) and the endothelin receptor type A (ETAR) are discussed in more detail. Extracellular vesicles are another novel player to possess disease processes. Fibroblasts are a key effector cell in SSc. Therefore, the current review will provide an overview about their plasticity in the phenotype and function. Promising nuclear receptors as key regulators of transcriptional programmes will be introduced as well as epigenetic modifications, which are pivotal to maintain the profibrotic fibroblast phenotype independent of external stimuli. Fibroblasts from SSc patients exhibit a specific signalling and reactivate developmental pathways and stem cell maintenance such as by employing hedgehog and WNT, which promote fibroblast-to-myofibroblast transition and extracellular matrix generation. Pharmacological interventions, although for other indications, are already in clinical use to address pathologic signalling.
系统性硬化症（SSc）是一种系统性自身免疫性疾病，具有炎症、血管病变和纤维化等关键特征。本文基于作者目前的工作和专业知识，聚焦于新兴领域。作者从环境因素的作用入手，为系统性硬化症发病机制的研究提供了一个层次结构。文中讨论了调节性自身抗体（自身抗体），它们是人体生理学的一部分，在系统性硬化症中尤其失调。对血管紧张素II 1型受体（AT1R）和内皮素A型受体（ETAR）的自身抗体进行了更详细的讨论。细胞外囊泡是参与疾病进程的另一个新因素。成纤维细胞是系统性硬化症中的关键效应细胞。因此，本综述将概述它们在表型和功能方面的可塑性。还将介绍作为转录程序关键调节因子的有前景的核受体以及表观遗传修饰，它们对于维持成纤维细胞的促纤维化表型至关重要，且不依赖于外部刺激。系统性硬化症患者的成纤维细胞表现出特定的信号传导，并重新激活发育途径和干细胞维持，例如通过利用刺猬信号通路和WNT信号通路，这些通路促进成纤维细胞向肌成纤维细胞的转变和细胞外基质的生成。尽管用于其他适应症，但药理学干预已在临床中用于解决病理信号传导问题。
