A novel myelin P0-specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy.
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.
Louvet
Cédric
C
Diabetes Center and the Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Kabre
Beniwende G
BG
Davini
Dan W
DW
Martinier
Nicolas
N
Su
Maureen A
MA
DeVoss
Jason J
JJ
Rosenthal
Wendy L
WL
Anderson
Mark S
MS
Bour-Jordan
Hélène
H
Bluestone
Jeffrey A
JA
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*
D016207:Cytokines; D000939:Epitopes; D018993:Myelin P0 Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta