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

作者：Scally Stephen W; Petersen Jan; Law Soi Cheng; Dudek Nadine L; Nel Hendrik J; Loh Khai Lee; Wijeyewickrema Lakshmi C; Eckle Sidonia B G; van Heemst Jurgen; Pike Robert N; McCluskey James; Toes Rene E; La Gruta Nicole L; Purcell Anthony W^*; Reid Hugh H; Thomas Ranjeny; Rossjohn Jamie

来源：Journal of Experimental Medicine, 2013, 210(12): 2569-2582.

DOI：10.1084/jem.20131241

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.

• 出版日期2013-11-18