Current view on the pathogenic role of anti-citrullinated protein antibodies in rheumatoid arthritis

Abstract

Epidemiological findings suggest a potential role for anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) pathogenesis. ACPA-positive RA is associated with unique genetical and environmental risk factors, in contrast to seronegative RA. ACPA-positive healthy individuals are at risk of developing RA and can develop joint pain and bone loss already before disease onset. ACPA injection triggered bone loss and pain-like behaviour in mice and, in the presence of additional arthritis inducers, exacerbated joint inflammation. In cell culture experiments, ACPAs could bind to and modulate a variety of cellular targets, such as macrophages, osteoclasts, synovial fibroblasts, neutrophil granulocytes, mast cells, dendritic cells and platelets, further underlying a potential role for these autoantibodies in triggering pathogenic pathways and providing clues for their mechanisms of action. Patient-derived ACPA clones have been characterised by unique cellular effects and multiple ways to act on the target cells. ACPAs might directly induce stimulatory signals by ligating key citrullinated cell surface molecules or, alternatively, act as immune complexes on Fc receptors and potentially other molecules that recognise carbohydrate moieties. On the contrary to experimentally manufactured ACPA clones, patient-derived ACPAs are highly promiscuous and cross-reactive, suggesting a simultaneous binding to a range of functionally relevant and irrelevant targets. Moreover, several ACPA clones recognise carbamylated or acetylated targets as well. These features complicate the identification and description of ACPA-induced pathogenic mechanisms. In the current review, we summarise recent data on the functional properties of patient-derived ACPAs and present mechanistic models on how these antibodies might contribute to RA pathogenesis.

Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy

“…In the search for a potential mechanism underlying the SME modulation by ACPAs, we evaluated the potential involvement of FcR, previously reported to mediate the effects of these autoantibodies in leucocyte activation. 53 The blockage of FcR prevented the downregulation of SME induced by ACPAs, underlying the role of these receptors on such effects.…”

Anti-citrullinated Protein Antibody Generation, Pathogenesis, Clinical Application, and Prospects

“…When NETs release a large amount of citrullinated antigens to drive ACPA production, the immune complexes containing ACPAs can form more NETs. Then, the immune complexes interact with the FCγ receptor (FCγR) on other neutrophils, releasing degrading enzymes and reactive oxygen species, ACPAs and citrullination promote programmed cell death, leading to autoantigen release ( 13 – 15 ) ( Figure 1 ). In RA patients' peripheral blood, ACPAs stimulate neutrophils to release PAD enzymes.…”

“…After some additional arthritogenic triggers, citrulline-specific B cells may receive T cell help, inducing an inflammatory autoimmune response (“the second hit”) ( 32 ). Then, ACPA levels increase, antibody diversity expands, and the ACPA response matures ( 13 ).…”

“…Moreover, a weak correlation between the ACPA titer level and disease activity was observed and fluctuation in the ACPA titer level could predict relapse in patients with RA remission. According to Anca Catrina's review, when individuals reach RA diagnosis, the ACPA repertoire remains relatively stable over time with small changes in ACPA levels and only occasional seroconversion ( 13 ).…”

Role of autoantibodies in the diagnosis and prognosis of interstitial lung disease in autoimmune rheumatic disorders

“… 8 These autoantibodies are thought to be pathogenic, because they might directly induce stimulatory signals by ligating key citrullinated cell surface molecules or, alternatively, act as immune complexes on Fc receptors. 98 A number of studies have revealed pathogenic processes to the onset of synovitis in RA, and production of RA autoantibodies precedes the onset of RA. 99 Specifically, in a genetically predisposed host, environmental insults, epigenetic modifications and post-translational modifications can lead to loss of immune tolerance with subsequent production of autoantibodies, including RF and ACPA.…”