Mireille Sebbag

Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins

Formation of the epitopes recognized by the rheumatoid arthritis (RA)‐specific autoantibodies to citrullinated proteins (ACPA) on filaggrin and on the α‐ and β‐chains of fibrin, their synovial target, requires conversion of their arginyl residues into citrullyl residues, but is also affected by their amino‐acyl environment. Using competition with five citrullinated filaggrin‐derived peptides bearing major ACPA epitopes, we confirmed the close cross‐reactivity between filaggrin and citrullinated fibrin. To identify the sequential epitopes recognized on fibrin by ACPA, 71u2004citrullinated 15‐mer peptides derived from all the sites of the α‐ and β‐chains of fibrin harboring arginyl residues were tested by ELISA using ACPA‐positive RA sera exhibiting different reactivity profiles to the five filaggrin peptides. We identified 18u2004fibrin‐derived peptides bearing ACPA epitopes. Regarding the ability of fibrinogen arginyl residues to be citrullinated in vitro, 11u2004of the peptides likely correspond to in vivo targeted epitopes. Two out of them bear major epitopes and are located in the central globular domain of the protein. In the synovial tissue, fibrin citrullination and ACPA binding could impair fibrin degradation by plasmin. The immunological conflict between ACPA and fibrin could therefore sustain synovial inflammation not only via pro‐inflammatory effector mechanisms but also via impairment of fibrinolysis.