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- and 
-Chains of Fibrin1
*
Department of Biology and Pathology of the Cell, Institut National de la Santé et de la Recherche Médicale Contrat Jeune Formation 96-02, Toulouse-Purpan School of Medicine, University Toulouse III (Institut Fédératif de Recherche 30, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique-Université Paul Sabatier-Centre Hospitalier Universitaire), Toulouse, France; and
Department of Bioactivity Regulation, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
IgG antifilaggrin autoantibodies (AFA) are the most specific
serological markers of rheumatoid arthritis. In epithelial tissues,
they recognize citrulline-bearing epitopes present on various molecular
forms of (pro)filaggrin. Histological analysis of rheumatoid synovial
membranes with an Ab to citrulline showed labeling of interstitial
amorphous deposits and mononuclear cells of various types.
Immunochemical analysis of exhaustive sequential extracts of the same
tissues showed that they contain several deiminated (citrulline
containing) proteins. Among them, two proteins, p64–78 and p55–61,
present in urea-DTT and guanidine extracts, were shown by
immunoblotting to be specifically targeted by AFA. By amino-terminal
sequencing the proteins were identified as deiminated forms of the 
-
and 
-chains of fibrin, respectively. Their identity was confirmed
using several Abs specific for the A- and/or to the B-chain of
fibrin(ogen). Moreover, AFA-positive rheumatoid arthritis (RA) sera and
purified AFA were highly reactive to the A- and B-chains of human
fibrinogen only after deimination of the molecules by a
peptidylarginine deiminase. Autoantibodies affinity purified from a
pool of RA sera onto deiminated fibrinogen were reactive toward all of
the epithelial and synovial targets of AFA. This confirmed that the
autoantibodies to the deiminated A-and B-chains of fibrinogen,
the autoantibodies to the synovial proteins p64–78 and p55–61, and,
lastly, AFA, constitute largely overlapping autoantibody populations.
These results show that deiminated forms of fibrin deposited in the
rheumatoid synovial membranes are the major target of AFA. They suggest
that autoimmunization against deiminated fibrin is a critical step in
RA pathogenesis.
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O Meyer, C Labarre, M Dougados, P. Goupille, A Cantagrel, A Dubois, P Nicaise-Roland, J Sibilia, and B Combe Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage Ann Rheum Dis, February 1, 2003; 62(2): 120 - 126. [Abstract] [Full Text] [PDF]
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O. Sanchez-Pernaute, M. J. Lopez-Armada, E. Calvo, I. Diez-Ortego, R. Largo, J. Egido, and G. Herrero-Beaumont Fibrin generated in the synovial fluid activates intimal cells from their apical surface: a sequential morphological study in antigen-induced arthritis Rheumatology, January 1, 2003; 42(1): 19 - 25. [Abstract] [Full Text] [PDF]
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R. Fritsch, D. Eselbock, K. Skriner, B. Jahn-Schmid, C. Scheinecker, B. Bohle, M. Tohidast-Akrad, S. Hayer, J. Neumuller, S. Pinol-Roma, et al. Characterization of Autoreactive T Cells to the Autoantigens Heterogeneous Nuclear Ribonucleoprotein A2 (RA33) and Filaggrin in Patients with Rheumatoid Arthritis J. Immunol., July 15, 2002; 169(2): 1068 - 1076. [Abstract] [Full Text] [PDF]
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T Avcin, R Cimaz, F Falcini, F Zulian, G Martini, G Simonini, V Porenta-Besic, G Cecchini, M O Borghi, and P L Meroni Prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis Ann Rheum Dis, July 1, 2002; 61(7): 608 - 611. [Abstract] [Full Text] [PDF]
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L Nogueira, M Sebbag, C Vincent, M Arnaud, B Fournie, A Cantagrel, M Jolivet, and G Serre Performance of two ELISAs for antifilaggrin autoantibodies, using either affinity purified or deiminated recombinant human filaggrin, in the diagnosis of rheumatoid arthritis Ann Rheum Dis, September 1, 2001; 60(9): 882 - 887. [Abstract] [Full Text] [PDF]
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