Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen

Arthritis Rheum. 2005 Nov;52(11):3424-32. doi: 10.1002/art.21391.


Objective: Antibodies directed against citrullinated fibrinogen are highly specific for rheumatoid arthritis (RA). This study was undertaken to test whether RA-associated HLA-DR alleles are associated with anti-citrullinated fibrinogen in RA patient sera and whether replacement of arginyl by citrullyl residues on fibrinogen peptides modifies their binding to HLA-DR molecules and their recognition by T cells.

Methods: Antikeratin, antifilaggrin, and anti-citrullinated fibrinogen antibodies were assayed in RA patients who had undergone HLA-DR typing. Direct assays were performed to investigate binding of citrullinated or native fibrinogen peptides (encompassing the entire alpha- and beta-chains of fibrinogen) to purified HLA-DR molecules. T cell proliferative responses to citrullinated or native fibrinogen peptides were measured in RA patients and controls.

Results: HLA-DRB1*0404 was associated with anti-citrullinated fibrinogen in RA sera (P = 0.002). For the RA-associated alleles HLA-DRB1*0401 and HLA-DR1, there was a nonsignificant trend toward association (P = 0.07). Multiple peptides from the alpha- and beta-chains of fibrinogen bound many HLA-DR alleles; DRB1*0404 was the best fibrinogen peptide binder. Citrullination did not influence fibrinogen peptide binding to HLA-DR or fibrinogen peptide recognition by T cells. Peripheral blood T cells that recognized native or citrullinated fibrinogen peptides were common in RA patients but not in healthy controls.

Conclusion: The RA-associated HLA-DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen. DRB1*0401 and DRB1*01 tend to be associated with anti-citrullinated fibrinogen, but this is not statistically significant. Citrullination of fibrinogen peptide does not influence peptide-DR-T cell interaction. Finally, T cell proliferation in response to citrullinated or uncitrullinated fibrinogen peptides is frequent in RA patients and very infrequent in controls.

Publication types

  • Multicenter Study

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Arginine / chemistry
  • Arginine / genetics
  • Arginine / metabolism
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • Autoantibodies / analysis*
  • Autoantibodies / chemistry
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Female
  • Genetic Predisposition to Disease
  • HLA-DR Antigens / genetics*
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / pathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / immunology*
  • Peptides, Cyclic / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / pathology


  • Autoantibodies
  • HLA-DR Antigens
  • Peptides, Cyclic
  • cyclic citrullinated peptide
  • Arginine