The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin

IgG antifilaggrin autoantibodies (AFA) are the most specific serological ma rkers of rheumatoid arthritis. In epithelial tissues, they recognize citrul line-bearing epitopes present on various molecular forms of (pro)filaggrin. Histological analysis of rheumatoid synovial membranes with an Ab to citru lline showed labeling of interstitial amorphous deposits and mononuclear ce lls of various types. Immunochemical analysis of exhaustive sequential extr acts of the same tissues showed that they contain several deiminated (citru lline containing) proteins. Among them, two proteins, p64-78 and p55-61, pr esent in urea-DTT and guanidine extracts, were shown by immunoblotting to b e specifically targeted by AFA, By amino-terminal sequencing the proteins w ere identified as deiminated forms of the alpha- and beta -chains of fibrin , respectively, Their identity was confirmed using several Abs specific for the A alpha -and/or to the B beta -chain of fibrin(ogen), Moreover, AFA-po sitive rheumatoid arthritis (RA) sera and purified AFA were highly reactive to the A alpha- and B beta -chains of human fibrinogen only after deiminat ion of the molecules by a peptidylarginine deiminase, Autoantibodies affini ty purified from a pool of RA sera onto deiminated fibrinogen were reactive toward all of the epithelial and synovial targets of AFA, This confirmed t hat the autoantibodies to the deiminated A alpha -and B beta -chains of fib rinogen, the autoantibodies to the synovial proteins p64-78 and p55-61, and , lastly, AFA, constitute largely overlapping autoantibody populations. The se results show that deiminated forms of fibrin deposited in the rheumatoid synovial membranes are the major target of AFA, They suggest that autoimmu nization against deiminated fibrin is a critical step in RA pathogenesis.