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Nat Commun. 2015 May 5;6:6681. doi: 10.1038/ncomms7681.

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

Author information

1
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
2
Department of Physics, University of Cyprus, 2109 Nicosia, Cyprus.
3
Faculty of Agricultural Technology, Technological Educational Institute of Ioanian Islands, Argostoli, Cephallonia 28100, Greece.
4
Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
5
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, 1066 CX Amsterdam, The Netherlands.
6
Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta 47100, Greece.

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.

PMID:
25942574
DOI:
10.1038/ncomms7681
[Indexed for MEDLINE]

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