Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis

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.

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“…RA is known to be associated with specific autoantibodies, in particular the anti-citrullinated protein antibodies (ACPA) [ 1 – 3 , 6 ]. Studies in multiple populations have clearly shown that ACPA and other RA-associated autoantibodies are detectable months to years prior to the onset of clinically detectable articular and systemic inflammation [ 6 , 7 ].…”

“…RA is known to be associated with specific autoantibodies, in particular the anti-citrullinated protein antibodies (ACPA) [ 1 – 3 , 6 ]. Studies in multiple populations have clearly shown that ACPA and other RA-associated autoantibodies are detectable months to years prior to the onset of clinically detectable articular and systemic inflammation [ 6 , 7 ]. Although the pathogenic role of these autoantibodies continues to be debated, the detection of preclinical ACPA seropositivity has led to the hypothesis that interventions during this stage may serve to substantially reduce the severity of the disease and delay or even prevent disease onset [ 6 , 7 ].…”

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

“…Although not necessarily required for the development of RA, autoAbs can readily be found many years before the onset of symptomatic disease in the evolution model of RA [ 107 , 108 , 109 ]. During the presymptomatic phase of the disease, B cells undergo a series of selection, expansion, epitope spreading and antibody maturation processes [ 22 , 29 ], providing physicians an opportunity for early detection and prevention of the disease.…”

“…Following the discovery of multiple protein candidates eligible for peptidyl arginine deiminase (PAD) citrullination, “RA citrullinome”, referring to the collection of hundreds of citrullinated proteins identified in the serum and synovial fluid of RA patients, was introduced to the field of RA research in recent decades [ 14 , 15 , 16 , 17 , 18 ]. With its superb diagnostic specificity, immunopathogenic relevance and excellent clinical correlations [ 19 , 20 , 21 , 22 ], ACPAs were included in the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) RA classification criteria [ 23 ]. Alongside the classical RA autoAb RF, ACPA was also considered an important hallmark of the disease in the past decade.…”

“…The pathogenic roles of RA-associated autoAbs have been critically reviewed by us and other researchers [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In this review, we summarize the three most important RA-associated autoAbs, namely, RF, ACPA and anti-CarP Ab, regarding their distinct characteristics and clinical applications in the early diagnosis and prognosis prediction of RA.…”