Autoimmunity in rheumatoid arthritis: different antigens-common principles

Since the identification of antibodies directed against citrullinated protein antibodies (ACPA) as specific serological markers for rheumatoid arthritis (RA) the insight into the pathogenesis of RA has made significant progress. It is now realised that RA does not represent one disease entity, as ACPA-positive and ACPA-negative RA differ in several important aspects. For example, the most prominent genetic risk factors, the human leucocyte antigen shared epitope alleles only predispose to ACPA-positive RA, but not to ACPA-negative disease. Likewise, ACPA-positive RA is characterised by a more severe disease course as well as by a lower chance to enter drug-free remission. More recently, it became apparent that next to ACPA, another autoantibody system is also present in RA patients that is directed against a structurally similar determinant. These antibodies recognise carbamylated proteins and thus are called anticarbamylated protein (anti-CarP) antibodies. During carbamylation lysine residues are post-translationally modified to a homocitrulline, the antigenic identity crucial for recognition by anti-CarP antibodies. In this review we will discuss novel insight into the immune responses directed against citrullinated and carbamylated proteins.