Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis.
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.
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Jurgen
J
van Heemst
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Diahann T S L
DT
Jansen
Department of Physics, University of Cyprus, 2109 Nicosia, Cyprus.
Savvas
S
Polydorides
Faculty of Agricultural Technology, Technological Educational Institute of Ioanian Islands, Argostoli, Cephallonia 28100, Greece.
Antonis K
AK
Moustakas
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Marieke
M
Bax
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Anouk L
AL
Feitsma
Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Diënne G
DG
Bontrop-Elferink
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Martine
M
Baarse
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Diane
D
van der Woude
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, 1066 CX Amsterdam, The Netherlands.
Gert-Jan
GJ
Wolbink
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, 1066 CX Amsterdam, The Netherlands.
Theo
T
Rispens
Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Frits
F
Koning
Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
René R P
RR
de Vries
Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta 47100, Greece.
George K
GK
Papadopoulos
Department of Physics, University of Cyprus, 2109 Nicosia, Cyprus.
Georgios
G
Archontis
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Tom W
TW
Huizinga
Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
René E
RE
Toes
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000517:prevention & control*; D001324:Autoantigens / Q000276:immunology; D001419:Bacteria / Q000276:immunology*; D015153:Blotting, Western; D002956:Citrulline / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018448:Models, Immunological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D016596:Vinculin / Q000737:chemistry / Q000276:immunology*; D014780:Viruses / Q000276:immunology*
D001324:Autoantigens; D000939:Epitopes; D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059811:HLA-DRB1 Chains; D016596:Vinculin; D002956:Citrulline; D007371:Interferon-gamma