Journal article
A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis
SW Scally, J Petersen, SC Law, NL Dudek, HJ Nel, KL Loh, LC Wijeyewickrema, SBG Eckle, JV Heemst, RN Pike, J McCluskey, RE Toes, NL La Gruta, AW Purcell, HH Reid, R Thomas, J Rossjohn
Journal of Experimental Medicine | Published : 2013
DOI: 10.1084/jem.20131241
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 gener..
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Funding Acknowledgements
This research was supported by the National Health and Medical Research Council of Australia (NHMRC) and the Australian Research Council. A.W. Purcell was supported by an NHMRC Senior Research Fellowship; N.L. La Gruta was supported by a Sylvia and Charles Viertel Senior Medical Research Fellowship; A.W. Purcell was supported by an NHMRC SRF; J. Rossjohn was supported by an NHMRC Australia Fellowship; R. Thomas was supported by an ARC Future Fellowship and Arthritis Queensland.