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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.

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


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.

[Indexed for MEDLINE]

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