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Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis

Author

Listed:
  • Jurgen van Heemst

    (Leiden University Medical Center)

  • Diahann T. S. L. Jansen

    (Leiden University Medical Center)

  • Savvas Polydorides

    (University of Cyprus)

  • Antonis K. Moustakas

    (Faculty of Agricultural Technology, Technological Educational Institute of Ioanian Islands)

  • Marieke Bax

    (Leiden University Medical Center)

  • Anouk L. Feitsma

    (Leiden University Medical Center)

  • Diënne G. Bontrop-Elferink

    (Leiden University Medical Center)

  • Martine Baarse

    (Leiden University Medical Center)

  • Diane van der Woude

    (Leiden University Medical Center)

  • Gert-Jan Wolbink

    (Sanquin Research and Landsteiner Laboratory, Academic Medical Center)

  • Theo Rispens

    (Sanquin Research and Landsteiner Laboratory, Academic Medical Center)

  • Frits Koning

    (Leiden University Medical Center)

  • René R. P. de Vries

    (Leiden University Medical Center)

  • George K. Papadopoulos

    (Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology)

  • Georgios Archontis

    (University of Cyprus)

  • Tom W. Huizinga

    (Leiden University Medical Center)

  • René E. Toes

    (Leiden University Medical Center)

Abstract

The HLA locus is the strongest risk factor for anti-citrullinated protein antibody (ACPA)+ rheumatoid arthritis (RA). Despite considerable efforts in the last 35 years, this association is poorly understood. Here we identify (citrullinated) vinculin, present in the joints of ACPA+ RA patients, as an autoantigen targeted by ACPA and CD4+ T cells. These T cells recognize an epitope with the core sequence DERAA, which is also found in many microbes and in protective HLA-DRB1*13 molecules, presented by predisposing HLA-DQ molecules. Moreover, these T cells crossreact with vinculin-derived and microbial-derived DERAA epitopes. Intriguingly, DERAA-directed T cells are not detected in HLA-DRB1*13+ donors, indicating that the DERAA epitope from HLA-DRB1*13 mediates (thymic) tolerance in these donors and explaining the protective effects associated with HLA-DRB1*13. Together our data indicate the involvement of pathogen-induced DERAA-directed T cells in the HLA–RA association and provide a molecular basis for the contribution of protective/predisposing HLA alleles.

Suggested Citation

  • Jurgen van Heemst & Diahann T. S. L. Jansen & Savvas Polydorides & Antonis K. Moustakas & Marieke Bax & Anouk L. Feitsma & Diënne G. Bontrop-Elferink & Martine Baarse & Diane van der Woude & Gert-Jan , 2015. "Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7681
    DOI: 10.1038/ncomms7681
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