Research ArticleRheumatoid Arthritis

NETs Are a Source of Citrullinated Autoantigens and Stimulate Inflammatory Responses in Rheumatoid Arthritis

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Science Translational Medicine  27 Mar 2013:
Vol. 5, Issue 178, pp. 178ra40
DOI: 10.1126/scitranslmed.3005580

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Autoantigens Slip Through the NET

Autoimmune diseases are caused when the body’s immune system attacks the very tissues it’s supposed to protect. Yet, what exactly induces this loss of tolerance to self remains murky. For some autoimmune diseases, autoantigens—cellular targets of the immune response—have been identified, although it remains unclear how these normally intracellular proteins are exposed to the immune response. One hypothesis as to how these proteins may be externalized is through the excretion of neutrophil extracellular traps (NETosis). NETosis is thought to be involved in neutrophil response to bacteria, but the secretion of self-antigens in the context of inflammatory stimuli may boost autoimmune response. Now, Khandpur et al. look at the role of NETosis in rheumatoid arthritis.

Autoantibodies to citrullinated antigens (ACPAs) are thought to be pathogenic in rheumatoid arthritis. The authors observed increased NETosis in patients with rheumatoid arthritis compared with both healthy controls and patients with non-autoimmune osteoarthritis. Indeed, NETosis correlated with levels of ACPA, and ACPA actually altered the makeup of the proteins secreted by neutrophils. NETs from rheumatoid arthritis patients contained citrullinated proteins, and these NETs enhanced the inflammatory response in fibroblasts from inflamed joints. Thus, altered NETosis in rheumatoid arthritis patients may contribute to the pathogenesis of disease.