The antigen specificity of the rheumatoid arthritis-associated ACPA directed to citrullinated fibrin is very closely restricted

J Autoimmun. 2011 Dec;37(4):263-72. doi: 10.1016/j.jaut.2011.07.003. Epub 2011 Aug 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody Specificity
  • Antigen-Antibody Complex / metabolism
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • Autoantigens / immunology
  • Citrulline / chemistry
  • Enzyme-Linked Immunosorbent Assay
  • Epitope Mapping
  • Fibrin / chemistry
  • Fibrin / immunology
  • Fibrin / metabolism*
  • Humans
  • Immunodominant Epitopes / immunology
  • Immunodominant Epitopes / metabolism*
  • Models, Chemical
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism*
  • Protein Conformation
  • Synovial Membrane / immunology


  • Antigen-Antibody Complex
  • Autoantibodies
  • Autoantigens
  • Immunodominant Epitopes
  • Peptide Fragments
  • Citrulline
  • Fibrin