title: Role of a Novel Human Leukocyte Antigen-DQA1*01:02;DRB1*15:01 Mixed Isotype Heterodimer in the Pathogenesis of "Humanized" Multiple Sclerosis-like Disease.
abstract: Gene-wide association and candidate gene studies indicate that the greatest effect on multiple sclerosis (MS) risk is driven by the HLA-DRB1*15:01 allele within the HLA-DR15 haplotype (HLA-DRB1*15:01-DQA1*01:02-DQB1*0602-DRB5*01:01). Nevertheless, linkage disequilibrium makes it difficult to define, without functional studies, whether the functionally relevant effect derives from DRB1*15:01 only, from its neighboring DQA1*01:02-DQB1*06:02 or DRB5*01:01 genes of HLA-DR15 haplotype, or from their combinations or epistatic interactions. Here, we analyzed the impact of the different HLA-DR15 haplotype alleles on disease susceptibility in a new "humanized" model of MS induced in HLA-transgenic (Tg) mice by human oligodendrocyte-specific protein (OSP)/claudin-11 (hOSP), one of the bona fide potential primary target antigens in MS. We show that the hOSP-associated MS-like disease is dominated by the DRB1*15:01 allele not only as the DRA1*01:01;DRB1*15:01 isotypic heterodimer but also, unexpectedly, as a functional DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. The contribution of HLA-DQA1/DRB1 mixed isotype heterodimer to OSP pathogenesis was revealed in (DRB1*1501xDQB1*0602)F1 double-Tg mice immunized with hOSP(142-161) peptide, where the encephalitogenic potential of prevalent DRB1*1501/hOSP(142-161)-reactive Th1/Th17 cells is hindered due to a single amino acid difference in the OSP(142-161) region between humans and mice; this impedes binding of DRB1*1501 to the mouse OSP(142-161) epitope in the mouse CNS while exposing functional binding of mouse OSP(142-161) to DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. This study, which shows for the first time a functional HLA-DQA1/DRB1 mixed isotype heterodimer and its potential association with disease susceptibility, provides a rationale for a potential effect on MS risk from DQA1*01:02 through functional DQA1*01:02;DRB1*15:01 antigen presentation. Furthermore, it highlights a potential contribution to MS risk also from interisotypic combination between products of neighboring HLA-DR15 haplotype alleles, in this case the DQA1/DRB1 combination.
authors.affiliation: From the Departments of Immunology and.
authors.forename: Nathali
authors.initials: N
authors.lastname: Kaushansky
authors.affiliation: Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Eisenstein
authors.affiliation: From the Departments of Immunology and.
authors.forename: Sigalit
authors.initials: S
authors.lastname: Boura-Halfon
authors.affiliation: the Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Bjarke Endel
authors.initials: BE
authors.lastname: Hansen
authors.affiliation: the Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Claus Henrik
authors.initials: CH
authors.lastname: Nielsen
authors.affiliation: the Department of Neurology, Barzilai Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Ashkelon 78278, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Milo
authors.affiliation: the Department of Neurological Rehabilitation, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel, the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Zeilig
authors.affiliation: the Center for Brain Research, Department of Neuroimmunology, Medical University of Vienna, 1090 Vienna, Austria, and.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: the Department of Medicine, Imperial College, Hammersmith Hospital, London W12 0HS, United Kingdom.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
authors.affiliation: From the Departments of Immunology and avi.ben-nun@weizmann.ac.il.
authors.forename: Avraham
authors.initials: A
authors.lastname: Ben-Nun
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057167:Claudins / Q000737:chemistry; D019281:Dimerization; D004843:Epistasis, Genetic; D059848:HLA-DQ alpha-Chains / Q000235:genetics / Q000276:immunology*; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology*; D017386:Sequence Homology, Amino Acid
chemical_list: C120453:CLDN11 protein, human; D057167:Claudins; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D059811:HLA-DRB1 Chains
keywords: multiple sclerosis, HLA transgenic mice, T-cell, autoimmune disease, peptides, HLA class II, OSP/claudin-11