title: The antigen specificity of the rheumatoid arthritis-associated ACPA directed to citrullinated fibrin is very closely restricted.
abstract: The major targets of the disease-specific autoantibodies to citrullinated proteins (ACPA) in synovium of rheumatoid arthritis (RA) patients are borne by the citrullinated α- and β-chains of fibrin. We demonstrated that ACPA target a limited set of citrullinated fibrin peptides and particularly four multicitrullinated peptides which present the major epitopes. In this study, we established the clear immunodominance of the peptides α36-50Cit(38,42) and β60-74Cit(60,72,74) which were recognised by 51/81 (63%) and 61/81 (75%) of ACPA-positive patients, respectively, more than 90% recognising one, the other or both peptides. We also identified the citrullyl residues αCit(42), βCit(72) and βCit(74) as essential for antigenicity, and at a lesser degree αCit(38). Then, we assayed on overlapping 7-mer peptides encompassing the sequences of the two peptides, 3 series of sera recognising either α36-50Cit(38,42) or β60-74Cit(60,72,74) or both peptides. In each series, the reactivity profiles of the sera, largely superimposable, allowed identification of the two 4/5-mer overlapping epitopes (α: VECit(42)HQ and α': Cit(38)VVE), and the single 5-mer epitope (β: GYCit(72)ACit(74)), all located to a flexible globular domain of fibrin on a topological 3D model. In conclusion, we demonstrated that only 3 immunodominant epitopes are targeted by ACPA on citrullinated fibrin stressing their actual oligoclonality. However, the reactivity to the 3 epitopes distinguishes three subgroups of patients. The closely restricted antigen specificity suggests that the autoimmune reaction to citrullinated fibrin is antigen-driven. The accessibility of the epitopes reinforces the hypothesis of a pathogenic role for ACPA via immune complexe formation in the synovial tissue.
authors.affiliation: Laboratory of "Epidermis Differentiation and Rheumatoid Autoimmunity", UMR 5165 CNRS-Toulouse III University, Purpan Hospital, Place du Dr Baylac, TSA 40031, 31059 Toulouse cedex 9, France. cristina.iobagiu@ch-roanne.fr
authors.forename: Cristina
authors.initials: C
authors.lastname: Iobagiu
authors.forename: Anna
authors.initials: A
authors.lastname: Magyar
authors.forename: Leonor
authors.initials: L
authors.lastname: Nogueira
authors.forename: Martin
authors.initials: M
authors.lastname: Cornillet
authors.forename: Mireille
authors.initials: M
authors.lastname: Sebbag
authors.forename: Jacques
authors.initials: J
authors.lastname: Arnaud
authors.forename: Ferenc
authors.initials: F
authors.lastname: Hudecz
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
mesh_terms: D000918:Antibody Specificity; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D002956:Citrulline / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D005337:Fibrin / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism*; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011487:Protein Conformation; D013583:Synovial Membrane / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D002956:Citrulline; D005337:Fibrin