Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan.
Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Japan.
Front Immunol. 2022 May 24;13:900638. doi: 10.3389/fimmu.2022.900638. eCollection 2022.
Systemic sclerosis (SSc) is an autoimmune disease that is characterized by vascular damage and fibrosis. Both clinical manifestations and immunological disturbances are diverse according to the disease duration. Particularly, changes in immunological processes are prominent in the early phase of SSc. The orchestration of several subsets of immune cells promotes autoimmune responses and inflammation, and eventually stimulates pro-fibrotic processes. Many reports have indicated that CD4 T cells play pivotal roles in pathogenesis in the early phase of SSc. In particular, the pathogenic roles of regulatory T (Treg) cells have been investigated. Although the results were controversial, recent reports suggested an increase of Treg cells in the early phase of SSc patients. Treg cells secrete transforming growth factor-β (TGF-β), which promotes myofibroblast activation and fibrosis. In addition, the dysfunction of Treg cells in the early phase of SSc was reported, which results in the development of autoimmunity and inflammation. Notably, Treg cells have the plasticity to convert to T-helper17 (Th17) cells under pro-inflammatory conditions. Th17 cells secrete IL-17A, which could also promote myofibroblast transformation and fibrosis and contributes to vasculopathy, although the issue is still controversial. Our recent transcriptomic comparison between the early and late phases of SSc revealed a clear difference of gene expression patterns only in Treg cells. The gene signature of an activated Treg cell subpopulation was expanded in the early phase of SSc and the oxidative phosphorylation pathway was enhanced, which can promote Th17 differentiation. And this result was accompanied by the increase in Th17 cells frequency. Therefore, an imbalance between Treg and Th17 cells could also have an important role in the pathogenesis of the early phase of SSc. In this review, we outlined the roles of Treg cells in the early phase of SSc, summarizing the data of both human and mouse models. The contributions of Treg cells to autoimmunity, vasculopathy, and fibrosis were revealed, based on the dysfunction and imbalance of Treg cells. We also referred to the potential development in treatment strategies in SSc.
系统性硬化症（SSc）是一种自身免疫性疾病，其特征为血管损伤和纤维化。根据疾病持续时间，临床表现和免疫紊乱均多种多样。特别是，在 SSc 的早期阶段，免疫过程的变化尤为明显。几种免疫细胞亚群的协调促进自身免疫反应和炎症，最终刺激促纤维化过程。许多报道表明，CD4 T 细胞在 SSc 的早期发病机制中起关键作用。特别是，调节性 T（Treg）细胞的致病作用已被研究。尽管结果存在争议，但最近的报道表明，在 SSc 患者的早期阶段 Treg 细胞增加。Treg 细胞分泌转化生长因子-β（TGF-β），可促进肌成纤维细胞活化和纤维化。此外，还报道了 SSc 早期 Treg 细胞的功能障碍，这导致自身免疫和炎症的发展。值得注意的是，Treg 细胞在促炎条件下可转化为 T 辅助 17（Th17）细胞。Th17 细胞分泌 IL-17A，也可促进肌成纤维细胞转化和纤维化，并有助于血管病变，尽管该问题仍存在争议。我们最近对 SSc 早期和晚期之间的转录组比较显示，仅在 Treg 细胞中就存在明显不同的基因表达模式。在 SSc 的早期阶段，激活的 Treg 细胞亚群的基因特征扩大，氧化磷酸化途径增强，这可以促进 Th17 分化。并且该结果伴随着 Th17 细胞频率的增加。因此，Treg 和 Th17 细胞之间的失衡也可能在 SSc 的早期发病机制中起重要作用。在这篇综述中，我们概述了 Treg 细胞在 SSc 早期阶段的作用，总结了人类和小鼠模型的数据。基于 Treg 细胞的功能障碍和失衡，揭示了 Treg 细胞对自身免疫，血管病变和纤维化的贡献。我们还提到了 SSc 治疗策略的潜在发展。
