title: Oligodendrocyte death results in immune-mediated CNS demyelination.
abstract: Although multiple sclerosis is a common neurological disorder, the origin of the autoimmune response against myelin, which is the characteristic feature of the disease, remains unclear. To investigate whether oligodendrocyte death could cause this autoimmune response, we examined the oligodendrocyte ablation Plp1-CreER(T);ROSA26-eGFP-DTA (DTA) mouse model. Approximately 30 weeks after recovering from oligodendrocyte loss and demyelination, DTA mice develop a fatal secondary disease characterized by extensive myelin and axonal loss. Strikingly, late-onset disease was associated with increased numbers of T lymphocytes in the CNS and myelin oligodendrocyte glycoprotein (MOG)-specific T cells in lymphoid organs. Transfer of T cells derived from DTA mice to naive recipients resulted in neurological defects that correlated with CNS white matter inflammation. Furthermore, immune tolerization against MOG ameliorated symptoms. Overall, these data indicate that oligodendrocyte death is sufficient to trigger an adaptive autoimmune response against myelin, suggesting that a similar process can occur in the pathogenesis of multiple sclerosis.
authors.affiliation: Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Traka
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Derrick P
authors.initials: DP
authors.lastname: McCarthy
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.affiliation: Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015551:Autoimmunity / Q000276:immunology*; D002452:Cell Count; D016923:Cell Death / Q000276:immunology*; D020278:Demyelinating Autoimmune Diseases, CNS / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D009836:Oligodendroglia; D013601:T-Lymphocytes / Q000276:immunology*; D013629:Tamoxifen / Q000494:pharmacology; D066127:White Matter
chemical_list: D018931:Antineoplastic Agents, Hormonal; D063308:Myelin-Oligodendrocyte Glycoprotein; D013629:Tamoxifen