title: Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment.
abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein/peptide autoantibodies (ACPAs). Citrulline derives from arginine by peptidyl arginine deiminases, and ACPAs are directed against different citrullinated antigens, including fibrinogen, fibronectin, α-enolase, collagen type II, histones. ACPAs are present in two thirds of RA patients have higher specificity than RF for RA, and are associated with joint radiographic damage and extra-articular manifestations and they are detected years before the onset clinical arthritis. Recent studies suggest that citrullinated antigens are most likely arthritogenic autoantigens in RA. ACPA production is associated with the HLA-DRB1 shared epitope (HLA-DRB1 SE) and accounts for the well-known RA-HLA-DRB1 SE association, as T cells recognize citrullinated peptides. Smoking and periodontitis, known environmental risk factors for RA promote protein citrullination and ACPA production. Cirullinated proteins are capable of inducing arthritis in transgenic mice carrying HLA-DRB1 SE genes, and ACPAs induce macrophage TNF-α production, osteoclastogenesis and complement activation. They also induce the formation of neutrophil extracellular traps (NETs). NETs, increased in RA, are a source of citrullinated autoantigens in RA and induce fibroblast interleukin-8 production. This knowledge is likely to have therapeutic implications, as there is a need of matching therapy with patient profile. Abatacept, a T cell activation modulator, is the best therapy for ACPA(+) RA patients, although clinical data are sparse at present. Rituximab, a monoclonal antibody that depletes B cells, is also the best therapy for ACPA(+) RA patients, and clinical data support this view.
authors.affiliation: Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis 41110, Larissa, Greece; Center for Molecular Medicine, Old Dominion University, 23529 Norfolk, VA, USA. Electronic address: lsakkas@med.uth.gr.
authors.forename: Lazaros I
authors.initials: LI
authors.lastname: Sakkas
authors.affiliation: Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis 41110, Larissa, Greece; Division of Transplantation Immunology and Mucosal Biology, Kings College London School of Medicine, SE5 9RS London, UK. Electronic address: bogdanos@med.uth.gr.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Bogdanos
authors.affiliation: Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis 41110, Larissa, Greece. Electronic address: katsiari@med.uth.gr.
authors.forename: Christina
authors.initials: C
authors.lastname: Katsiari
authors.affiliation: Center for Molecular Medicine, Old Dominion University, 23529 Norfolk, VA, USA. Electronic address: cplatsoukas@odu.edu.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Platsoucas
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002956:Citrulline / Q000276:immunology*; D006801:Humans; D010455:Peptides / Q000276:immunology
chemical_list: D001324:Autoantigens; D010455:Peptides; D002956:Citrulline
keywords: Anticitrullinated antibodies; Autoantigens; Citrullinated antigens; Rheumatoid arthritis; Treatment