Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
J Clin Invest. 2020 May 1;130(5):2451-2464. doi: 10.1172/JCI131700.
Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.
系统性硬化症（SSc）是一种自身免疫性纤维性疾病，其发病机制尚不清楚，且缺乏有效的治疗方法。我们对 35 名未经治疗的早期弥漫性系统性硬化症患者的皮肤中的 T 细胞浸润进行了定量分析，结果表明 CD4+细胞毒性 T 细胞和 CD8+T 细胞显著参与了这些浸润。我们还观察到 SSc 组织中凋亡细胞的积累，这表明反复的细胞死亡可能导致纤维化疾病中的组织损伤和重塑。在 SSc 中，表达 HLA-DR 的内皮细胞是凋亡的常见靶标，这与该疾病患者中明显的血管病变一致。在系统性硬化症患者中，循环效应细胞群的细胞毒性 CD4+T 细胞克隆扩增，表现出增强代谢活性的特征。这些数据表明，细胞毒性 T 细胞可能诱导系统性硬化症中内皮细胞和其他细胞的凋亡。免疫细胞介导的细胞丢失可能会导致过度活跃的组织修复过程，从而导致纤维化和组织功能障碍。
