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Joint Bone Spine
Volume 71, n° 6
pages 493-502 (novembre 2004)
Doi : 10.1016/j.jbspin.2004.07.004
Received : 12 July 2004 ;  accepted : 12 July 2004
Clinical and pathophysiological significance of the autoimmune response to citrullinated proteins in rheumatoid arthritis
 

Mireille Sebbag a, Sabine Chapuy-Regaud a, Isabelle Auger b, Elisabeth Petit-Texeira c, Cyril Clavel a, Leonor Nogueira a, Christian Vincent a, François Cornélis c, Jean Roudier b, Guy Serre a,
a Faculté de Médecine, Purpan-IFR30, Unité “Différenciation Épidermique et Auto-immunité Rhumatoïde”, UMR 5165 CNRS-Toulouse III Université, (CNRS-Inserm-Université Paul Sabatier-CHU de Toulouse), Place du Docteur Baylac, 31059 Toulouse cedex, France 
b UMR 639 Inserm, Faculté de Médecine, Marseille, France 
c GenHotel, Laboratoire de Recherche Européen pour la Polyarthrite Rhumatoïde, Evry-Génopôle, France 

*Corresponding author. Tel.: +33-5-61-77-23-95; fax: +33-5-61-77-76-20.

Lecture presented at the research symposium “Molecular bases of the autoimmune response to citrullinated proteins in rheumatoid arthritis” at the 17th Meeting of the “Société Française de Rhumatologie”, CNIT-La Défense, Paris, November 2004

Abstract

Rheumatoid arthritis (RA) is the most frequent human autoimmune disease, affecting about 1% of the adult population worldwide. A better knowledge of the autoimmune mechanisms involved is essential. We identified the epithelial targets of various autoantibodies specifically associated to RA, as variants of (pro)filaggrin. We also showed that these targets correspond to deiminated (“citrullinated”) proteins, of which arginyl residues have been posttranslationally transformed into citrullyl residues by a peptidylarginine deiminase (PAD). Moreover, we and others established that citrullyl residues are indispensable elements of the epitopes recognized by these autoantibodies but only in the context of specific aminoacid sequences. We also demonstrated that these autoantibodies to citrullinated proteins (ACPA) are secreted by plasma cells of the synovial tissue and that their major targets correspond to citrullinated forms of the ⍺- and β-chains of fibrin, abundant in the tissue. These results have allowed the development of new efficient immunochemical methods for the detection of ACPA. Some of them are already commercially available. These new methods have permitted the high diagnostic value of ACPA which are present very early in the course of the disease, and also their prognostic value, to be confirmed. ACPA detection should therefore prove to be also a very valuable tool to guide the choice of therapeutic strategies, from the earliest stages of the disease. The synthesis of ACPA in the rheumatoid synovial tissue and the existence therein of a specific antigenic target constitute a strong argument for the involvement of this specific immunological conflict in the pathophysiology of RA. Indeed, it could lead to activation of effector mechanisms with pro-inflammatory effects, thus to formation in the tissue of new fibrin deposits, secondarily citrullinated. We therefore, propose a new pathophysiological model accounting for the self-maintenance and chronicity of rheumatoid inflammation. Numerous questions about the pathophysiological significance of the autoimmune response to deiminated proteins in RA remain to be answered to confirm this model.

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Keywords : RA, Citrullinated peptides




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