title: A functional and structural basis for TCR cross-reactivity in multiple sclerosis.
abstract: The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB1*1501, DRB5*0101 and DQB1*0602 are in strong linkage disequilibrium, making it difficult to determine which is the principal MS risk gene. Here we show that together the DRB1 and DRB5 loci may influence susceptibility to MS. We demonstrate that a T cell receptor (TCR) from an MS patient recognized both a DRB1*1501-restricted myelin basic protein (MBP) and DRB5*0101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB5*0101-EBV peptide complex revealed a marked degree of structural equivalence to the DRB1*1501-MBP peptide complex at the surface presented for TCR recognition. This provides structural evidence for molecular mimicry involving HLA molecules. The structural details suggest an explanation for the preponderance of MHC class II associations in HLA-associated diseases.
authors.affiliation: Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
authors.forename: Heather L E
authors.initials: HL
authors.lastname: Lang
authors.forename: Helle
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Shinji
authors.initials: S
authors.lastname: Ikemizu
authors.forename: Christina
authors.initials: C
authors.lastname: Andersson
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.forename: Lars
authors.initials: L
authors.lastname: Madsen
authors.forename: Peter
authors.initials: P
authors.lastname: Hjorth
authors.forename: Leif
authors.initials: L
authors.lastname: Sondergaard
authors.forename: Arne
authors.initials: A
authors.lastname: Svejgaard
authors.forename: Kai
authors.initials: K
authors.lastname: Wucherpfennig
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: John I
authors.initials: JI
authors.lastname: Bell
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D006684:HLA-DR Antigens / Q000737:chemistry / Q000276:immunology*; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology*; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta