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

• Published in: The Journal of experimental medicine Vol. 210; no. 12; pp. 2569 - 2582
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 18.11.2013
• Subjects: Aggrecans - genetics; Aggrecans - immunology; Aggrecans - metabolism; Amino Acid Sequence; Animals; Antigen Presentation; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Autoantigens - chemistry; Autoantigens - genetics; Autoantigens - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Citrulline - metabolism; Epitopes - chemistry; Epitopes - genetics; Epitopes - metabolism; Genetic Association Studies; HLA-DR beta-Chains - chemistry; HLA-DR beta-Chains - genetics; HLA-DR beta-Chains - metabolism; HLA-DR4 Antigen - chemistry; HLA-DR4 Antigen - genetics; HLA-DR4 Antigen - metabolism; HLA-DRB1 Chains - chemistry; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - metabolism; Humans; Mice; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Polymorphism, Genetic; Vimentin - genetics; Vimentin - immunology; Vimentin - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20131241

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.