Crossreactivity to Vinculin and Microbes Provides a Molecular Basis for HLA-based Protection Against Rheumatoid Arthritis

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigen Presentation / immunology
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / prevention & control*
  • Autoantigens / immunology
  • Bacteria / immunology*
  • Blotting, Western
  • Citrulline / metabolism
  • Cross Reactions / immunology*
  • Enzyme-Linked Immunospot Assay
  • Epitopes / chemistry
  • Epitopes / immunology
  • HLA Antigens / 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
  • Vinculin / immunology*
  • Viruses / immunology*

Substances

  • Autoantigens
  • Epitopes
  • HLA Antigens
  • HLA-DQ Antigens
  • HLA-DRB1 Chains
  • Vinculin
  • Citrulline
  • Interferon-gamma