Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity

The chronic inflammatory joint disease rheumatoid arthritis (RA) is characterised by synovial inflammation and pannus formation, which can lead to severe destruction of cartilage and bone. Several self proteins have been suggested as disease-driving autoantigens, and the presence of autoantibodies with different specificities in patients with RA (reviewed in [1,2]) supports the hypothesis of an autoimmune aetiology. Rheumatoid factor has for a long time been the best-described RA-associated antibody marker, recognising the Fc part of IgG molecules. However, another class of autoantibodies has lately gained attention, namely antibodies directed against proteins containing the non-standard amino acid citrulline [3,4].Citrulline is generated by the deimination of arginine, a post-translational modification occurring during apoptosis as well as during the terminal differentiation of cells, in both healthy and arthritic individuals [5,6]. Citrullination is catalysed by a family of calcium-dependent enzymes named peptidyl arginine deiminase (PAD, EC 3.5.3.15) (reviewed in [7]). These enzymes are present in several different cell and tissue types, including inflammatory cells (PAD2 [8-10] and PAD4 [10-12]). PAD4 has been detected in granulocytes infiltrating the synovial tissue in a mouse model of arthritis [13] and this enzyme, together with PAD2, has also been demonstrated in macrophages from synovial fluid of patients with RA [10].The best-described citrulline-reactive autoantibodies associated with RA are the following: anti-perinuclear factor [14,15] and anti-keratin autoantibodies [16,17], both directed against citrullinated filaggrin [18]; anti-Sa autoantibodies [19] directed against citrullinated vimentin [20]; and antibodies against cyclic citrullinated peptide (anti-CCP) [21,22]. These latter autoantibodies have a sensitivity of up to 80% and a specificity of 98% in patients with RA [1,22]. Besides this high specificity, these markers are present early in disease