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

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 Wolbink, Theo Rispens, Frits Koning, René R. P. de Vries, George K. Papadopoulos, Georgios Archontis, Tom W. Huizinga and René E. Toes ()
Additional contact information
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

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7681

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