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Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles
  1. O Snir1,
  2. M Widhe1,
  3. C von Spee1,
  4. J Lindberg2,
  5. L Padyukov1,
  6. K Lundberg3,
  7. Å Engström4,
  8. P J Venables3,
  9. J Lundeberg2,
  10. R Holmdahl5,
  11. L Klareskog1,
  12. V Malmström1
  1. 1
    Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Solna, Stockholm, Sweden
  2. 2
    School of Biotechnology, Department of Gene Technology, AlbaNova University Centre, Royal Institute of Technology, Stockholm, Sweden
  3. 3
    Kennedy Institute of Rheumatology, Imperial College, London, UK
  4. 4
    Uppsala Biomedical Centre, IMBIM, Uppsala, Sweden
  5. 5
    Medical Inflammation Research, Lund University, Lund, Sweden
  1. Dr V Malmström, Rheumatology Unit, Department of Medicine, Centre for Molecular Medicine L8:04, SE-17176 Stockholm, Sweden: vivianne.malmstrom{at}


Background: Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles.

Objective: To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles.

Methods: Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, α-enolase peptide-1 and the C1-epitope of type II collagen (C1III). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed.

Results: 72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients’ sera and in 41% for both citrullinated α-enolase peptide-1 and citrullinated C1III. These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles.

Conclusions: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.

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  • Competing interests: None.

  • Funding: This study was supported by Margaretha af Ugglas Foundation, the Swedish Research Council and an EU FP6 project, AutoCure LSHB CT-2006-018661, 2. This publication reflects only the authors’ views; the European Community is not liable for any use that may be made of the information herein.

  • Ethics approval: Approved by the ethical review board of Karolinska University Hospital.

  • OS and MW contributed equally to this work