1. Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis.
- Author
-
van Heemst J, Jansen DT, Polydorides S, Moustakas AK, Bax M, Feitsma AL, Bontrop-Elferink DG, Baarse M, van der Woude D, Wolbink GJ, Rispens T, Koning F, de Vries RR, Papadopoulos GK, Archontis G, Huizinga TW, and Toes RE
- Subjects
- Amino Acid Sequence, Antigen Presentation immunology, Autoantigens immunology, Blotting, Western, Citrulline metabolism, Enzyme-Linked Immunospot Assay, Epitopes chemistry, Epitopes immunology, HLA-DQ Antigens immunology, HLA-DRB1 Chains immunology, Humans, Interferon-gamma metabolism, Models, Immunological, Models, Molecular, Molecular Sequence Data, T-Lymphocytes immunology, Tissue Donors, Vinculin chemistry, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid prevention & control, Bacteria immunology, Cross Reactions immunology, HLA Antigens immunology, Vinculin immunology, Viruses immunology
- 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.
- Published
- 2015
- Full Text
- View/download PDF