From perinuclear factor to citrulline, a target structure for autoantibodies in rheumatoid arthritis

Abstract

Antiperinuclear factor (APF) and the so-called antikeratin (AKA), have been described 37 and 22 years ago, respectively. Now, their diagnostic value in Rheumatoid Arthritis (RA) was confirmed on thousands of patients. In the past few years the molecular targets of these RA-specific serum IgG antibodies were identified : first those of AKA were shown to be acidic variants of filaggrin in human epidermis and (pro)filaggrin-related proteins in rat oesophagus epithelium ; secondarily the target of APF in human buccal mucosa cells was demonstrated to correspond to tissue-specific forms of (pro)filaggrin. APF and AKA were proved to constitute two overlapping subgroups of antibodies belonging to a same family of antifilaggrin autoantibodies (AFA). All these AFA-targetted proteins were demonstrated to be deiminated i.e. having their arginyl residues (arginines involved in peptidic bonds) transformed into citrullyl residues (citrullines). This post-translational enzymatic modification is due to a peptidyl-arginine deiminase. AFA are unreactive with native recombinant human filaggrin but become highly reactive after enzymatic deimination of the protein. Moreover synthetic peptides derived from the human filaggrin sequence are reactive with AFA only when their arginyl residues have been substituted by citrullyl residues (citrullinated peptides). Therefore AFA are directed to peptidic epitopes in which citrullyl residues play a pivotal role, nevertheless the neighbouring residues are important since certain are permissive and participate to generation of AFA epitopes whereas others are non-permissive and make the reactivity with AFA impossible. Identification of the molecular targets of AFA allowed the development of new tests for their detection, using either (pro)filaggrin extracted from epithelia or deiminated recombinant filaggrins and/or filaggrin-derived citrullinated peptides. Several of these new tests prove to be highly efficient in the diagnosis of RA and largely more performant than the reference APF and AKA tests. They show that at least 2 out of 3 RA patients develop the very specific antifilaggrin B autoimmunity. In rheumatoid synovial tissue, (pro)filaggrin was confirmed to be absent, however several deiminated proteins were detected. Among them, only two proteins were highly reactive with AFA. They were identified as the alpha and beta chains of fibrin. Deiminated fibrin therefore appears as the major synovial target of AFA and probably correspond to their genuine target. In RA patients, the proportion of AFA among IgG was recently found to be largely higher in the synovial interstitium than in synovial fluid and serum, moreover AFA were shown to be secreted by plasma cells of the rheumatoid pannus. These results strongly suggest that the chronic conflict between the locally secreted AFA / antifibrin autoantibodies and the fibrin deposits particularly prominent in the RA synovium, play a central role in the pathophysiology of RA.