Department of Immunology and Microbiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
Division of Rheumatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
J Autoimmun. 2018 Mar;88:1-10. doi: 10.1016/j.jaut.2017.10.008.
How and why we break tolerance to self-proteins still remains a largely unanswered question. Neutrophils have been identified as a rich source of autoantigens in a wide array of autoimmune diseases that arise as a consequence of different environmental and genetic factors, e.g. rheumatoid arthritis (RA), lupus, vasculitis, cystic fibrosis (CF) etc. Specifically, neutrophil extracellular trap (NET) formation has been identified as a link between innate and adaptive immune responses in autoimmunity. Autoantigens including neutrophil granular proteins (targeted by anti-neutrophil cytoplasmic antibodies, ANCA) as well as post-translationally modified proteins, i.e. citrullinated and carbamylated proteins targeted by anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein antibodies (ACarPA), respectively, localize to the NETs. Moreover, NETs provide stimuli to dendritic cells that potentiate adaptive autoimmune responses. However, while NETs promote inflammation and appear to induce humoral autoreactivity across autoimmune diseases, the antigen specificity of autoantibodies found in these disorders is striking. These unique autoantigen signatures suggest that not all NETs are created equal and that the environment in which NETs arise shapes their disease-specific character. In this review article, we discuss the effects of different stimuli on the mechanism of NET formation as well as how they contribute to antigen specificity in the breaking of immune tolerance. Specifically, we compare and contrast the autoreactive nature of NETs in two settings of chronic airway inflammation: one triggered by smoking, a recognized environmental NET stimulus in RA patients, and one mediated by Pseudomonas aeruginosa, the most prevalent lung pathogen in CF patients. Finally, we draw attention to novel findings that, together with the specific environmental/chemical stimuli, should be taken into account when investigating how and why antigen specificity arises in the context of NET formation.
自身蛋白耐受的形成机制和原因仍不清楚。中性粒细胞已被确定为多种自身免疫性疾病的自身抗原的丰富来源，这些疾病是由不同的环境和遗传因素引起的，例如类风湿关节炎（RA）、狼疮、血管炎、囊性纤维化（CF）等。具体来说，中性粒细胞胞外诱捕网（NET）的形成已被确定为自身免疫中固有和适应性免疫反应之间的联系。自身抗原包括中性粒细胞颗粒蛋白（针对抗中性粒细胞胞质抗体，ANCA）以及翻译后修饰的蛋白，即瓜氨酸化和氨甲酰化蛋白，分别针对抗瓜氨酸化蛋白抗体（ACPA）和抗氨甲酰化蛋白抗体（ACarPA）。此外，NET 向树突状细胞提供刺激，增强适应性自身免疫反应。然而，尽管 NET 促进炎症并似乎在自身免疫疾病中诱导体液自身反应，但在这些疾病中发现的自身抗体的抗原特异性引人注目。这些独特的自身抗原特征表明，并非所有 NET 都是平等产生的，并且 NET 产生的环境会塑造其疾病特异性特征。在这篇综述文章中，我们讨论了不同刺激对 NET 形成机制的影响，以及它们如何导致免疫耐受破坏中的抗原特异性。具体来说，我们比较和对比了慢性气道炎症两种情况下 NET 的自身反应性质：一种由吸烟触发，吸烟是 RA 患者公认的环境 NET 刺激物，另一种由铜绿假单胞菌介导，铜绿假单胞菌是 CF 患者肺部最常见的病原体。最后，我们提请注意新的发现，这些发现连同特定的环境/化学刺激物，在研究 NET 形成背景下抗原特异性是如何以及为何产生时应该考虑在内。
