title: A novel myelin P0-specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy.
abstract: Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4(+) T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4(+) T cell hybridomas were generated from inflamed tissue-derived CD4(+) T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0-specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3-5 wk of age. This abrupt disease was associated with the production of interferon gamma by P0-specific T cells and a lack of CD4(+) Foxp3(+) regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy.
authors.affiliation: Diabetes Center and the Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Cédric
authors.initials: C
authors.lastname: Louvet
authors.forename: Beniwende G
authors.initials: BG
authors.lastname: Kabre
authors.forename: Dan W
authors.initials: DW
authors.lastname: Davini
authors.forename: Nicolas
authors.initials: N
authors.lastname: Martinier
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Su
authors.forename: Jason J
authors.initials: JJ
authors.lastname: DeVoss
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Rosenthal
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.forename: Hélène
authors.initials: H
authors.lastname: Bour-Jordan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D000939:Epitopes; D006825:Hybridomas; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018993:Myelin P0 Protein / Q000378:metabolism*; D010525:Peripheral Nerves / Q000276:immunology / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*
chemical_list: D016207:Cytokines; D000939:Epitopes; D018993:Myelin P0 Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta