The role of synovial citrullinated proteins in the pathophysiology of rheumatoid arthritis

Abstract

Autoantibodies targeting citrullinated proteins are generated in the majority of rheumatoid arthritis (RA) patients and generally detectable prior to disease onset. Increasing evidence indicate that these autoantibodies play a role in the pathophysiology of RA and this is most likely related to the interaction with their target proteins, which are indeed present in the inflamed joints of RA patients. Although protein citrullination is not a unique feature of joint inflammation in RA, the disease-specific production of anti-citrullinated protein antibodies will lead to the formation of immune complexes that may contribute to disease progression. This chapter starts with the processes that are believed to mediate protein citrullination and anti-citrullinated protein antibody production in RA patients, as well as the main factors involved. Subsequently, several citrullinated proteins identified in the inflamed joint, fibrinogen, vimentin, alpha-enolase, fibronectin, apolipoprotein E, myeloid nuclear differentiation antigen and beta-actin, and their (possible) function in RA are described in more detail. Besides pathophysiological aspects, the diagnostic and prognostic value of antibodies to these citrullinated autoantigens is discussed. In addition to citrullination, another, though chemically related, posttranslational modification called carbamylation and antibodies to carbamylated proteins have recently been suggested to play a role in the pathophysiology of rheumatoid arthritis as well. Finally, this chapter summarizes our current knowledge on the role of citrullination in animal models for arthritis, which are used to obtain more detailed information on pathophysiological mechanisms.