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

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 and Rossjohn, Jamie (2013) A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. Journal of Experimental Medicine, 210 12: 2569-2582. doi:10.1084/jem.20131241

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Author 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
Title A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis
Journal name Journal of Experimental Medicine   Check publisher's open access policy
ISSN 0022-1007
1540-9538
Publication date 2013-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1084/jem.20131241
Open Access Status File (Publisher version)
Volume 210
Issue 12
Start page 2569
End page 2582
Total pages 14
Place of publication New York, NY United States
Publisher Rockefeller University Press
Language eng
Subject 2403 Immunology
2723 Immunology and Allergy
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 HLADRB1* 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 HLADRB1* 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.
Keyword Immunology
Medicine, Research & Experimental
Immunology
Research & Experimental Medicine
IMMUNOLOGY
MEDICINE, RESEARCH & EXPERIMENTAL
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
 
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