Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrin

Abstract

Rheumatoid arthritis (RA), a chronic inflammatory joint disease, develops in patients expressing particular HLA-DR alleles. RA patients' sera contain antibodies to a post-translationally modified form of fibrin on which arginyl residues are transformed in citrullins. We tested whether HLA-DR alleles influence the production of anti-citrullinated fibrin antibodies in RA patient sera and whether the replacement of arginyl residues by citrullyl residues on fibrin peptides could modify their binding to RA-associated HLA-DR molecules and their recognition by T cells in RA patients and controls. We found that RA-associated HLA-DR alleles are also associated with presence of anti-citrullinated fibrin antibodies in RA patient sera. Multiple peptides from the alpha and beta chain of fibrin are capable to bind many HLA-DR alleles. RA-associated HLA-DR alleles are good fibrin peptide binders. However, citrullination does not influence fibrin peptide binding to HLA-DR or fibrin peptide recognition by T cells. Finally, peripheral blood T cells that recognize native or citrullinated fibrin peptides are common in RA patients and very uncommon in normal controls. These results suggest that citrullination of fibrin has nothing to do with peptide/HLA-DR/T cell interaction and is merely involved in the definition of B-cell epitopes.