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

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.

• Authors: Jurgen van Heemst, Diahann T S L Jansen, Savvas Polydorides, Antonis K Moustakas, Marieke Bax, Anouk L Feitsma, Diënne G Bontrop-Elferink, Martine Baarse, Diane van der Woude, Gert-Jan Wolbink, Theo Rispens, Frits Koning, René R P de Vries, George K Papadopoulos, Georgios Archontis, Tom W Huizinga, René E Toes
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6681 (May 05 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25942574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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