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.