title: Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis.
abstract: This article reviews recent literature on the origin and pathogenic role of anticitrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA).
  
  
  
  ACPAs and ACPA-immune complexes interact with immune cells to facilitate articular inflammation. Findings from recent in vitro and in vivo studies are congruent with epidemiologic observations in RA supporting a pathogenic role of ACPAs.
  
  
  
  ACPAs target proteins/peptides with citrullinated epitopes and serve as informative RA biomarkers. ACPAs are generated within synovium and possibly at extra-articular sites prior to disease onset. Proximate to RA onset, critical qualitative and quantitative changes to ACPAs occur that drive proinflammatory responses. Unable to induce arthritis alone, the administration of ACPAs enhances the development and severity of inflammation in mice when a mild synovitis is already present. In vitro studies have elucidated several possible mechanisms linking ACPA to disease progression including: first, activation of inflammatory cells by ACPA-immune complexes; second, ACPA-mediated neutrophil cell death producing neutrophil extracellular traps, which drives inflammation and autoimmunity by releasing citrullinated autoantigen; and finally, direct binding of ACPAs to osteoclasts and resulting osteoclastogenesis. Together, these recent investigations have begun to elucidate the different mechanisms by which ACPAs may be directly pathogenic in RA.
authors.affiliation: Veterans Affairs Nebraska-Western Iowa Healthcare System and Division of Rheumatology and Immunology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Bryant R
authors.initials: BR
authors.lastname: England
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Thiele
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D010012:Osteogenesis / Q000276:immunology; D010456:Peptides, Cyclic / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology; D013585:Synovitis / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide