Institute of Integrative Biology, Biosciences Building, Crown Street, University of Liverpool, Liverpool L69 7ZB, UK.
Institute of Ageing and Chronic Disease, University Hospital Aintree, University of Liverpool, Longmoor Lane, Liverpool L9 7AL, UK.
Nat Rev Rheumatol. 2014 Oct;10(10):593-601. doi: 10.1038/nrrheum.2014.80. Epub 2014 Jun 10.
Of all cells implicated in the pathology of rheumatoid arthritis (RA), neutrophils possess the greatest cytotoxic potential, owing to their ability to release degradative enzymes and reactive oxygen species. Neutrophils also contribute to the cytokine and chemokine cascades that accompany inflammation, and regulate immune responses via cell-cell interactions. Emerging evidence suggests that neutrophils also have a previously unrecognised role in autoimmune diseases: neutrophils can release neutrophil extracellular traps (NETs) containing chromatin associated with granule enzymes, which not only kill extracellular microorganisms but also provide a source of autoantigens. For example, citrullinated proteins that can act as neoepitopes in loss of immune tolerance are generated by peptidylarginine deiminases, which replace arginine with citrulline residues, within neutrophils. Indeed, antibodies to citrullinated proteins can be detected before the onset of symptoms in patients with RA, and are predictive of erosive disease. Neutrophils from patients with RA have an increased tendency to form NETs containing citrullinated proteins, and sera from such patients contain autoantibodies that recognize these proteins. Thus, in addition to their cytotoxic and immunoregulatory role in RA, neutrophils may be a source of the autoantigens that drive the autoimmune processes underlying this disease.
在类风湿关节炎（RA）的病理过程中涉及到的所有细胞中，中性粒细胞由于其能够释放降解酶和活性氧物质，因此具有最大的细胞毒性潜力。中性粒细胞也有助于伴随炎症的细胞因子和趋化因子级联反应，并通过细胞间相互作用调节免疫反应。新出现的证据表明，中性粒细胞在自身免疫性疾病中也具有以前未被识别的作用：中性粒细胞可以释放含有与颗粒酶相关染色质的中性粒细胞细胞外陷阱（NETs），这些 NETs 不仅可以杀死细胞外微生物，还可以提供自身抗原的来源。例如，由肽基精氨酸脱亚氨酶产生的可以作为免疫耐受丧失中新表位的瓜氨酸化蛋白，用瓜氨酸残基取代精氨酸。事实上，在 RA 患者出现症状之前，就可以检测到针对瓜氨酸化蛋白的抗体，并且可以预测侵蚀性疾病。RA 患者的中性粒细胞形成含有瓜氨酸化蛋白的 NETs 的趋势增加，并且来自此类患者的血清中含有识别这些蛋白的自身抗体。因此，除了在 RA 中具有细胞毒性和免疫调节作用外，中性粒细胞也可能是驱动这种疾病自身免疫过程的自身抗原的来源。
