A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

作者：S.W. Scally, Jan Petersen, Soi Cheng Law, Nadine L. Dudek, Hendrik J. Nel, Khai Lee Loh, Lakshmi C. Wijeyewickrema, Sidonia B. G. Eckle, Jurgen van Heemst, Robert N. Pike, James McCluskey, René E. M. Toes, Nicole L. La Gruta, Anthony W. Purcell, Hugh H. Reid, Ranjeny Thomas, Jamie Rossjohn · 发表于：The Journal of Experimental Medicine · 年份：2013 · DOI：10.1084/jem.20131241 · 被引用次数：423 · 研究领域：T-cell and B-cell Immunology、Rheumatoid Arthritis Research and Therapies、Cell Adhesion Molecules Research

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01(+) individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4(+) T cells in the peripheral blood of HLA-DRB1*04:01(+) RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.