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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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
JournalJournal of Experimental Medicine
Volume210
Issue number12
DOIs
Publication statusPublished - 2013

Cite this

Scally, Stephen ; Petersen, Jan ; Law, Soi Cheng CHENG ; Dudek, Nadine Lee ; Nel, Hendrik J ; Loh, Khai Lee ; Wijeyewickrema, Lakshmi Carmel ; Eckle, Sidonia B G ; van Heemst, Jurgen ; Pike, Robert Neil ; McCluskey, James ; Toes, Rene E ; La Gruta, Nicole L ; Purcell, Anthony Wayne ; Reid, Hugh Harrington ; Thomas, Ranjeny ; Rossjohn, Jamie. / A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 12. pp. 2569 - 2582.
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title = "A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis",
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.",
author = "Stephen Scally and Jan Petersen and Law, {Soi Cheng CHENG} and Dudek, {Nadine Lee} and Nel, {Hendrik J} and Loh, {Khai Lee} and Wijeyewickrema, {Lakshmi Carmel} and Eckle, {Sidonia B G} and {van Heemst}, Jurgen and Pike, {Robert Neil} and James McCluskey and Toes, {Rene E} and {La Gruta}, {Nicole L} and Purcell, {Anthony Wayne} and Reid, {Hugh Harrington} and Ranjeny Thomas and Jamie Rossjohn",
year = "2013",
doi = "10.1084/jem.20131241",
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Scally, S, Petersen, J, Law, SCCHENG, Dudek, NL, Nel, HJ, Loh, KL, Wijeyewickrema, LC, Eckle, SBG, van Heemst, J, Pike, RN, McCluskey, J, Toes, RE, La Gruta, NL, Purcell, AW, Reid, HH, Thomas, R & Rossjohn, J 2013, 'A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis', Journal of Experimental Medicine, vol. 210, no. 12, pp. 2569 - 2582. https://doi.org/10.1084/jem.20131241

A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. / Scally, Stephen; Petersen, Jan; Law, Soi Cheng CHENG; Dudek, Nadine Lee; Nel, Hendrik J; Loh, Khai Lee; Wijeyewickrema, Lakshmi Carmel; Eckle, Sidonia B G; van Heemst, Jurgen; Pike, Robert Neil; McCluskey, James; Toes, Rene E; La Gruta, Nicole L; Purcell, Anthony Wayne; Reid, Hugh Harrington; Thomas, Ranjeny; Rossjohn, Jamie.

In: Journal of Experimental Medicine, Vol. 210, No. 12, 2013, p. 2569 - 2582.

Research output: Contribution to journalArticleResearchpeer-review

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

VL - 210

SP - 2569

EP - 2582

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

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