Abstract
Individuals with high anti-citrullinated protein antibody (ACPA) titers have an increased risk of developing rheumatoid arthritis (RA). Although our knowledge of the generation and production of ACPAs has continuously advanced during the past decade, our understanding on the pathogenic mechanisms of how ACPAs interact with immune cells to trigger articular inflammation is relatively limited. Citrullination disorders drive the generation and maintenance of ACPAs, with profound clinical significance in patients with RA. The loss of tolerance to citrullinated proteins, however, is essential for ACPAs to exert their pathogenicity. N-linked glycosylation, cross-reactivity and the structural interactions of ACPAs with their citrullinated antigens further direct their biological functions. Although questions remain in the pathogenicity of ACPAs acting as agonists for a receptor-mediated response, immune complex (IC) formation, complement system activation, crystallizable fragment gamma receptor (FcγR) activation, cross-reactivity to joint cartilage and neutrophil extracellular trap (NET)-related mechanisms have all been suggested recently. This paper presents a critical review of the characteristics and possible biological effects and mechanisms of the immunopathogenesis of ACPAs in patients with RA.
Highlights
Overview of anti-citrullinated protein antibody (ACPA) in Patients with Rheumatoid ArthritisRheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by synovial inflammation and joint destruction
Accumulating evidence suggests that ACPA seropositivity predicts a good response to rituximab [17,18,19], but is not an ideal biomarker to monitor the efficacy of methotrexate or tumor necrosis factor (TNF) inhibitors [20,21]
immune complex (IC) formed by the conjunction of ACPAs and citrullinated proteins followed by complement and FcγR activation are considered to play a role in ACPA immunopathogenesis [32,33]
Summary
Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by synovial inflammation and joint destruction. Accumulating evidence suggests that ACPA seropositivity predicts a good response to rituximab [17,18,19], but is not an ideal biomarker to monitor the efficacy of methotrexate or tumor necrosis factor (TNF) inhibitors [20,21]. Due to their high specificity and excellent clinical correlations, ACPAs have become the autoantibodies of attention in the field of RA research in recent decades [22]. We review the latest evidence, discuss several important characteristics of ACPAs, and focus on the interaction between ACPAs and active players in the development of RA
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