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

Stephen Scally, Jan Petersen, Soi Cheng CHENG Law, Nadine Lee Dudek, Hendrik J Nel, Khai Lee Loh, Lakshmi Carmel Wijeyewickrema, Sidonia B G Eckle, Jurgen van Heemst, Robert Neil Pike, James McCluskey, Rene E Toes, Nicole L La Gruta, Anthony Wayne Purcell, Hugh Harrington Reid, Ranjeny Thomas, Jamie Rossjohn

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204 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2569 - 2582
Number of pages14
JournalThe Journal of Experimental Medicine
Volume210
Issue number12
DOIs
Publication statusPublished - 2013

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