TY - JOUR
T1 - A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis
AU - Scally, Stephen
AU - Petersen, Jan
AU - Law, Soi Cheng CHENG
AU - Dudek, Nadine Lee
AU - Nel, Hendrik J
AU - Loh, Khai Lee
AU - Wijeyewickrema, Lakshmi Carmel
AU - Eckle, Sidonia B G
AU - van Heemst, Jurgen
AU - Pike, Robert Neil
AU - McCluskey, James
AU - Toes, Rene E
AU - La Gruta, Nicole L
AU - Purcell, Anthony Wayne
AU - Reid, Hugh Harrington
AU - Thomas, Ranjeny
AU - Rossjohn, Jamie
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://jem.rupress.org/content/210/12/2569.full.pdf+html
U2 - 10.1084/jem.20131241
DO - 10.1084/jem.20131241
M3 - Article
SN - 0022-1007
VL - 210
SP - 2569
EP - 2582
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -