NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.
Knight, Jason S.
Patel, Rajiv M.
Thompson, Paul R
Fox, David A.
Kaplan, Mariana J.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
Real-Time Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
Enzymes and Coenzymes
MetadataShow full item record
AbstractThe early events leading to the development of rheumatoid arthritis (RA) remain unclear, but formation of autoantibodies to citrullinated protein antigens (ACPAs) is considered a key pathogenic event. Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophil extracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context of immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers, and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and from patients with osteoarthritis (OA). Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules, and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. Indeed, during NETosis, neutrophils externalized the citrullinated autoantigens implicated in RA pathogenesis, and anti-citrullinated vimentin antibodies potently induced NET formation. Moreover, the inflammatory cytokines interleukin-17A (IL-17A) and tumor necrosis factor-alpha (TNF-alpha) induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease.
SourceSci Transl Med. 2013 Mar 27;5(178):178ra40. doi: 10.1126/scitranslmed.3005580. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/50015
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related ResourcesLink to Article in PubMed