title: Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule.
abstract: Rheumatoid arthritis (RA) is genetically associated with MHC class II molecules that contain the shared epitope. These MHC molecules may participate in disease pathogenesis by selectively binding arthritogenic peptides for presentation to autoreactive CD4(+) T cells. The nature of the arthritogenic Ag is not known, but recent work has identified posttranslationally modified proteins containing citrulline (deiminated arginine) as specific targets of the IgG Ab response in RA patients. To understand how citrulline might evoke an autoimmune reaction, we have studied T cell responses to citrulline-containing peptides in HLA-DRB1*0401 transgenic (DR4-IE tg) mice. In this study, we demonstrate that the conversion of arginine to citrulline at the peptide side-chain position interacting with the shared epitope significantly increases peptide-MHC affinity and leads to the activation CD4(+) T cells in DR4-IE tg mice. These results reveal how DRB1 alleles with the shared epitope could initiate an autoimmune response to citrullinated self-Ags in RA patients.
authors.affiliation: Department of Medicine, University of Western Ontario, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hill
authors.forename: Scott
authors.initials: S
authors.lastname: Southwood
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
authors.forename: David A
authors.initials: DA
authors.lastname: Bell
authors.forename: Ewa
authors.initials: E
authors.lastname: Cairns
mesh_terms: D000483:Alleles; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014746:Vimentin / Q000378:metabolism
chemical_list: D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010446:Peptide Fragments; D014746:Vimentin; D002956:Citrulline; D001120:Arginine