1. Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis
- Author
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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., Landsteiner Laboratory, and Archontis, Georgios Z. [0000-0002-7750-8641]
- Subjects
rheumatoid arthritis ,microorganism ,Models, Molecular ,Enzyme-Linked Immunospot Assay ,HLA DRB1 antigen ,peripheral blood mononuclear cell ,enzyme linked immunospot assay ,T-Lymphocytes ,General Physics and Astronomy ,Arthritis ,HLA DR antigen ,Autoantigens ,Epitope ,Western blotting ,immunology ,Arthritis, Rheumatoid ,Epitopes ,immune system diseases ,HLA Antigens ,antibody ,T lymphocyte ,HLA SE antigen ,molecular mimicry ,HLA DQ8 antigen ,cross reaction ,skin and connective tissue diseases ,Peptide sequence ,donor ,epitope ,Antigen Presentation ,Multidisciplinary ,biology ,HLA DQB1 antigen ,Vinculin ,bacterium ,molecular mechanics ,autoantigen ,Tissue Donors ,unclassified drug ,antigen recognition ,Blot ,risk factor ,Rheumatoid arthritis ,Viruses ,HLA DQ antigen ,gamma interferon ,HLA system ,musculoskeletal diseases ,HLA antigen ,HLA DQ5 antigen ,Blotting, Western ,Molecular Sequence Data ,virus ,Human leukocyte antigen ,Cross Reactions ,chemistry ,microbial activity ,Article ,General Biochemistry, Genetics and Molecular Biology ,HLA DQA1 antigen ,Interferon-gamma ,antigen ,HLA-DQ Antigens ,medicine ,Humans ,molecular analysis ,human ,Amino Acid Sequence ,Allele ,HLA DQ7 antigen ,CD4+ T lymphocyte ,nonhuman ,Bacteria ,vinculin ,human cell ,disease predisposition ,Models, Immunological ,General Chemistry ,biological model ,medicine.disease ,molecular dynamics ,amino acid sequence ,antigen presentation ,disability ,antigen presenting cell ,molecular genetics ,citrulline ,Immunology ,chemical structure ,biology.protein ,Citrulline ,protein ,metabolism ,pathogen ,HLA-DRB1 Chains - 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. 6 Cited By :21
- Published
- 2015