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

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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.

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