Autoantibodies to deiminated (citrullinated) forms of the α and β chains of fibrin (AhFibA), also known as antifilaggrin autoantibodies (AFA), are the most specific serological markers of rheumatoid arthritis (RA). Deimination is critical in generating the AhFibA epitopes and, in the synovial tissue (ST), deiminated fibrin is their major antigenic target. Existence of fibrin deimination specifically in RA patients could explain why the AhFibA response is RA specific.
Methods and Results
To explore such an association, the presence of deiminated fibrin in the ST was assessed in a series of 32 patients, 13 with RA and 19 with non-RA rheumatological disorders (controls). ST biopsies were collected in macroscopically inflamed areas identified under needle arthroscopy of the knee. Histopathological examination confirmed the existence of synovitis in all of the samples. The presence of deiminated fibrin was first assessed by immunoblotting of ST extracts using antibodies to citrullyl residues and to the α and β chains of fibrin, and AhFibA purified from a pool of RA sera. Deiminated fibrin was evidenced in all of the ST samples. Moreover, variations in the ratio of deiminated to total fibrin were not related to diagnosis. Immunohistochemical analysis, performed on adjacent synovial biopsy sections of 19 of the 32 patients, using antibodies to the β chain of fibrin and to citrullyl residues, allowed us to confirm the results obtained by immunoblotting, because deiminated fibrin was detected in six RA patients and six controls.
Our results show the presence of deiminated fibrin in the ST is not specific for RA and suggest that it is induced by ST inflammation. Moreover, they show the production of AhFibA is not a direct consequence of the presence of deiminated fibrin in the ST. Nonetheless, AhFibA are tightly associated with RA. Because they are also present very early in the disease course, linked to disease severity and produced in the ST, they probably play an important role in RA pathophysiology.