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.

Keywords: anti-citrullinated protein antibodies; arthritis; autoimmunity; rheumatoid.

Figure 1

Evolution of ACPA reactivities during RA progression. Humoral autoimmunity against citrullinated autoantigens can be triggered in response to environmental challenges at mucosal sites (such as cigarette smoking and bacterial infections) especially in individuals with a genetical background that is linked to RA susceptibility. Individuals carrying ACPAs in the circulation can remain disease free for long periods, suggesting that the initial antibody repertoire may not obviously trigger pathogenic pathways. Nevertheless, ACPAs in patients with RA typically accumulate very high number of mutations suggesting a progressive evolution of the ACPA repertoire, via somatic hypermutation and antigen-driven selection, which can ultimately lead to novel fine specificities that enable the targeting of key signalling molecules on cells that are characterised by a steady state protein citrullination. ACPAs might thus trigger certain pathogenic signals already before disease onset, such as pain and bone erosion, and potentially facilitate arthritis development in response to additional arthritogenic stimuli representing a ‘second hit’ for arthritis development. RA onset is associated with an increase in ACPA levels and a further expansion of the antibody diversity. Inflammation boosts protein citrullination, which can lead to increased immune complex formation and the appearance of novel autoantigens, enabling further types of pathogenic ACPA signals. ACPAs, anti-citrullinated protein antibodies; RA, rheumatoid arthritis.

Figure 2

ACPAs modulate cellular function by binding to cell surface proteins or by forming immune complexes. (A) ACPA binding to key citrullinated proteins on the cell surface might directly initiate signalling processes in the cells. (B) Alternatively, ACPAs can form immune complexes and activate FcRs. (C) Rheumatoid factor antibodies could enhance both mechanisms by crosslinking ACPA-antigen complexes and thereby increasing direct or FcR-mediated ACPA signals (the latter is illustrated). (D) Different ACPA-mediated pathways might concomitantly occur in the same cells that express functional ACPA targets and FcRs. (E) Autoantibody effects are frequently studied by using heat-aggregated immune complexes, bypassing the role of the antigens in the antibody-induced signalling. Such models have provided some important information but, at the same time, lack the ability to embrace other aspects such as the direct cell stimulation by ACPA ligation of cell surface proteins or whether the antibodies can form FcR stimulating ICs. ACPAs, anti-citrullinated protein antibodies.

Figure 3

Poly-specific ACPAs with specific functions. (A) ACPAs isolated from patients with rheumatoid arthritis typically recognise a very high number of citrullinated antigens in binding assays. However, each antibody is characterised by different affinities towards the individual antigens, which leads to their preferential binding to the highest affinity targets under physiological conditions. (B) ACPAs can directly stimulate cells by binding to a key functional target on the cell surface. Highly specific (dark blue) or poly-specific/promiscuous (light blue) autoantibodies can trigger similar activation signals, if the ligation of such surface molecules is sufficiently strong. Diversion of a promiscuous antibody to irrelevant targets could, however, decrease signal strength. Ligation of irrelevant surface antigens, either by highly specific or promiscuous antibodies will not trigger activation signals. (C) Promiscuity of the autoantibodies can facilitate immune complex formation and FcR binding. ACPAs, anti-citrullinated protein antibodies.