Department of Clinical Laboratory, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, 12N248C, Bethesda, MD, USA.
Clin Rev Allergy Immunol. 2021 Feb;60(1):1-16. doi: 10.1007/s12016-020-08816-3. Epub 2020 Nov 5.
Systemic rheumatic diseases are a heterogeneous group of disorders characterized by profound immune dysregulation. Recent discoveries have led to a significant resurgence of interest in neutrophils as shapers of immune dysregulation and as triggers of organ damage in rheumatic diseases. Neutrophils contribute to the initiation, promotion, and perpetuation of immune dysregulation through a variety of mechanisms including synthesis of proinflammatory cytokines, direct tissue damage through degranulation and synthesis of reactive oxygen species, and the formation of neutrophil extracellular traps (NETs). The identification of a subset of proinflammatory neutrophils, the low-density granulocytes (LDGs), which promote Th1 responses and cause endothelial dysfunction, has further strengthened the pathogenic role of neutrophils in various rheumatic diseases. The presence of autoantibodies targeting molecules commonly expressed in neutrophils suggests that neutrophils, particularly NETs, may be a source of autoantigens. An imbalance between NET formation and degradation, which leads to increased NET levels in the circulation and tissues, could enhance the exposure of the immune system to modified autoantigens, promote vascular disease, and increase tissue damage. This review will present an overview of recent advances in our understanding of how neutrophil dysregulation modulates the innate and adaptive immune responses in systemic rheumatic diseases and their putative contributions to pathogenicity. Understanding the potential pathogenic role of neutrophil dysregulation may provide better molecular candidates for therapeutic targeting, and ultimately promote improvements in the clinical outcomes in rheumatic diseases.
系统性风湿病是一组以深刻的免疫失调为特征的异质性疾病。最近的发现导致人们对中性粒细胞作为免疫失调形成者和风湿病器官损伤触发者的兴趣显著复苏。中性粒细胞通过多种机制促进免疫失调的发生、促进和持续，包括合成促炎细胞因子、脱颗粒和合成活性氧物质直接导致组织损伤，以及形成中性粒细胞胞外陷阱（NETs）。鉴定出促炎中性粒细胞的一个亚群，即低密粒细胞（LDGs），它们促进 Th1 反应并导致内皮功能障碍，进一步加强了中性粒细胞在各种风湿病中的致病作用。针对中性粒细胞中常见分子的自身抗体的存在表明，中性粒细胞，特别是 NETs，可能是自身抗原的来源。NET 形成和降解之间的失衡，导致循环和组织中 NET 水平升高，可能会增强免疫系统对修饰后的自身抗原的暴露，促进血管疾病，并增加组织损伤。这篇综述将概述我们对中性粒细胞失调如何调节系统性风湿病中的先天和适应性免疫反应及其对致病性的潜在贡献的最新认识。了解中性粒细胞失调的潜在致病作用可能为治疗靶点提供更好的分子候选物，并最终促进风湿病临床结局的改善。
