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

• DOI: 10.1038/ncomms7681
• Publication Date: 2015-05-05T14:56:37Z
• Authors: Jurgen van Heemst; Diahann T. S. L. ...; Savvas Polydorides; Antonis K. Moustakas; Marieke Bax; Anouk L. Feitsma; Diënne G. Bontrop...; Martine Baarse; Diane van der Woude; Gert-Jan Wolbink; Theo Rispens; Frits Koning; René R. P. de Vries; George K. Papadop...; Georgios Archontis; Tom W. Huizinga; René E. Toes
• Keywords: Vinculin

The HLA locus is the strongest risk factor for anti-citrullinated protein antibody (ACPA)+ rheumatoid arthritis (RA). Despite considerable efforts in last 35 years, this association poorly understood. Here we identify (citrullinated) vinculin, present joints of ACPA+ RA patients, as an autoantigen targeted by ACPA and CD4+ T cells. These cells recognize epitope with core sequence DERAA, which also found many microbes protective HLA-DRB1*13 molecules, presented predisposing HLA-DQ molecules. Moreover, these crossreact vinculin-derived microbial-derived DERAA epitopes. Intriguingly, DERAA-directed are not detected HLA-DRB1*13+ donors, indicating that from mediates (thymic) tolerance donors explaining effects associated HLA-DRB1*13. Together our data indicate involvement pathogen-induced HLA–RA provide a molecular basis contribution protective/predisposing alleles. Autoantibodies targeting citrunillated proteins common patients. authors show vinculin (a human protein) some microbial recognized antibodies CD4+T cells, response absent patients carrying allele.