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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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T Cantaert, P Coucke, L De Rycke, E M Veys, F De Keyser, and D Baeten Functional haplotypes of PADI4: relevance for rheumatoid arthritis specific synovial intracellular citrullinated proteins and anticitrullinated protein antibodies Ann Rheum Dis, September 1, 2005; 64(9): 1316 - 1320. [Abstract] [Full Text] [PDF]
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S. Chapuy-Regaud, M. Sebbag, D. Baeten, C. Clavel, C. Foulquier, F. De Keyser, and G. Serre Fibrin Deimination in Synovial Tissue Is Not Specific for Rheumatoid Arthritis but Commonly Occurs during Synovitides J. Immunol., April 15, 2005; 174(8): 5057 - 5064. [Abstract] [Full Text] [PDF]
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L Caponi, E Petit-Teixeira, M Sebbag, F Bongiorni, S Moscato, F Pratesi, C Pierlot, J Osorio, S Chapuy-Regaud, M Guerrin, et al. A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population Ann Rheum Dis, April 1, 2005; 64(4): 587 - 593. [Abstract] [Full Text] [PDF]
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X. Chang, R. Yamada, T. Sawada, A. Suzuki, Y. Kochi, and K. Yamamoto The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis Rheumatology, March 1, 2005; 44(3): 293 - 298. [Abstract] [Full Text] [PDF]
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X. Chang, R. Yamada, A. Suzuki, T. Sawada, S. Yoshino, S. Tokuhiro, and K. Yamamoto Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis Rheumatology, January 1, 2005; 44(1): 40 - 50. [Abstract] [Full Text] [PDF]
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O Kasapcopur, S Altun, M Aslan, S Karaarslan, A Kamburoglu-Goksel, S Saribas, N Arisoy, and B Kocazeybek Diagnostic accuracy of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis Ann Rheum Dis, December 1, 2004; 63(12): 1687 - 1689. [Abstract] [Full Text] [PDF]
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C Alessandri, M Bombardieri, N Papa, M Cinquini, L Magrini, A Tincani, and G Valesini Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNF{alpha} therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement Ann Rheum Dis, October 1, 2004; 63(10): 1218 - 1221. [Abstract] [Full Text] [PDF]
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A Kastbom, G Strandberg, A Lindroos, and T Skogh Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project) Ann Rheum Dis, September 1, 2004; 63(9): 1085 - 1089. [Abstract] [Full Text] [PDF]
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E R Vossenaar, T R D Radstake, A van der Heijden, M A M van Mansum, C Dieteren, D-J de Rooij, P Barrera, A J W Zendman, and W J van Venrooij Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages Ann Rheum Dis, April 1, 2004; 63(4): 373 - 381. [Abstract] [Full Text] [PDF]
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S Dubucquoi, E Solau-Gervais, D Lefranc, L Marguerie, J Sibilia, J Goetz, V Dutoit, A-L Fauchais, E Hachulla, R-M Flipo, et al. Evaluation of anti-citrullinated filaggrin antibodies as hallmarks for the diagnosis of rheumatic diseases Ann Rheum Dis, April 1, 2004; 63(4): 415 - 419. [Abstract] [Full Text] [PDF]
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O Sanchez-Pernaute, R Largo, E Calvo, M A Alvarez-Soria, J Egido, and G Herrero-Beaumont A fibrin based model for rheumatoid synovitis Ann Rheum Dis, December 1, 2003; 62(12): 1135 - 1138. [Abstract] [Full Text] [PDF]
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J. A. Hill, S. Southwood, A. Sette, A. M. Jevnikar, D. A. Bell, and E. Cairns Cutting Edge: The Conversion of Arginine to Citrulline Allows for a High-Affinity Peptide Interaction with the Rheumatoid Arthritis-Associated HLA-DRB1*0401 MHC Class II Molecule J. Immunol., July 15, 2003; 171(2): 538 - 541. [Abstract] [Full Text] [PDF]
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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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K. Nakashima, T. Hagiwara, and M. Yamada Nuclear Localization of Peptidylarginine Deiminase V and Histone Deimination in Granulocytes J. Biol. Chem., December 13, 2002; 277(51): 49562 - 49568. [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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