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.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scally
authors.forename: Jan
authors.initials: J
authors.lastname: Petersen
authors.forename: Soi Cheng
authors.initials: SC
authors.lastname: Law
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.forename: Hendrik J
authors.initials: HJ
authors.lastname: Nel
authors.forename: Khai Lee
authors.initials: KL
authors.lastname: Loh
authors.forename: Lakshmi C
authors.initials: LC
authors.lastname: Wijeyewickrema
authors.forename: Sidonia B G
authors.initials: SB
authors.lastname: Eckle
authors.forename: Jurgen
authors.initials: J
authors.lastname: van Heemst
authors.forename: Robert N
authors.initials: RN
authors.lastname: Pike
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Rene E
authors.initials: RE
authors.lastname: Toes
authors.forename: Nicole L
authors.initials: NL
authors.lastname: La Gruta
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D053674:Aggrecans / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056726:Genetic Association Studies; D059806:HLA-DR beta-Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D014746:Vimentin / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C508319:ACAN protein, human; D053674:Aggrecans; D001324:Autoantigens; D000939:Epitopes; D059806:HLA-DR beta-Chains; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; D014746:Vimentin; D002956:Citrulline