title: HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis.
abstract: To investigate the development of HLA-DR-associated autoimmune diseases, we generated transgenic (Tg) mice with HLA-DRA-IE alpha and HLA-DRB1*0401-IE beta chimeric genes. The transgene-encoded proteins consisted of antigen-binding domains from HLA-DRA and HLA-DRB1*0401 molecules and the remaining domains from the IE(d)-alpha and IE(d)-beta chains. The chimeric molecules showed the same antigen-binding specificity as HLA-DRB1*0401 molecules, and were functional in presenting antigens to T cells. The Tg mice were backcrossed to MHC class II-deficient (IA beta-, IE alpha-) mice to eliminate any effect of endogenous MHC class II genes on the development of autoimmune diseases. As expected, IA alpha beta or IE alpha beta molecules were not expressed in Tg mice. Moreover, cell-surface expression of endogenous IE beta associated with HLA-DRA-IE alpha was not detectable in several Tg mouse lines by flow cytometric analysis. The HLA-DRA-IE alpha/HLA-DRB1*0401-IE beta molecules rescued the development of CD4+ T cells in MHC class II-deficient mice, but T cells expressing V beta 5, V beta 11, and V beta 12 were specifically deleted. Tg mice were immunized with peptides, myelin basic protein (MBP) 87-106 and proteolipid protein (PLP) 175-192, that are considered to be immunodominant epitopes in HLA-DR4 individuals. PLP175-192 provoked a strong proliferative response of lymph node T cells from Tg mice, and caused inflammatory lesions in white matter of the CNS and symptoms of experimental allergic encephalomyelitis (EAE). Immunization with MBP87-106 elicited a very weak proliferative T cell response and caused mild EAE. Non-Tg mice immunized with either PLP175-192 or MBP87-106 did not develop EAE. These results demonstrated that a human MHC class II binding site alone can confer susceptibility to an experimentally induced murine autoimmune disease.
authors.affiliation: Department of Inflammation and Autoimmune Diseases, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: H J
authors.initials: HJ
authors.lastname: Bian
authors.forename: M
authors.initials: M
authors.lastname: Molina
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: Magram
authors.forename: E
authors.initials: E
authors.lastname: Saar
authors.forename: C
authors.initials: C
authors.lastname: Belunis
authors.forename: D R
authors.initials: DR
authors.lastname: Bolin
authors.forename: R
authors.initials: R
authors.lastname: Arceo
authors.forename: R
authors.initials: R
authors.lastname: Campbell
authors.forename: F
authors.initials: F
authors.lastname: Falcioni
authors.forename: D
authors.initials: D
authors.lastname: Vidović
authors.forename: J
authors.initials: J
authors.lastname: Hammer
authors.forename: Z A
authors.initials: ZA
authors.lastname: Nagy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000096:biosynthesis*; D059805:HLA-DR alpha-Chains; D015804:HLA-DR4 Antigen / Q000096:biosynthesis*; D059811:HLA-DRB1 Chains; D006801:Humans; D007249:Inflammation; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology; D009185:Myelin Proteins / Q000276:immunology; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D017931:DNA Primers; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D011993:Recombinant Fusion Proteins