Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis
Date
2015Author
Van Heemst, J.Jansen, D. T. S. L.
Polydorides, Savvas
Moustakas, Antonis K.
Bax, M.
Feitsma, A. L.
Bontrop-Elferink, D. G.
Baarse, M.
Van Der Woude, D.
Wolbink, G. -J
Rispens, T.
Koning, F.
De Vries, R. R. P.
Papadopoulos, George K.
Archontis, Georgios Z.
Huizinga, T. W.
Toes, R. E.
ISSN
2041-1723Source
Nature CommunicationsVolume
6Google Scholar check
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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.
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