title: Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis.
abstract: In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, immunization with myelin Ags leads to demyelination and paralysis. To investigate which molecules are crucial for the pathogenesis of EAE, we specifically assessed the roles of the death receptors Fas and TNF-R1. Mice lacking Fas expression in oligodendrocytes (ODCs) were generated and crossed to TNF-R1-deficient mice. To achieve specific deletion of a loxP-flanked fas allele in ODCs, we generated a new insertion transgene, expressing the Cre recombinase specifically in ODCs. Fas inactivation alone as well as the complete absence of TNF-R1 protected mice partially from EAE induced by the immunization with myelin ODC glycoprotein. The double-deficient mice, however, showed almost no clinical signs of EAE after immunization. Histological analysis revealed that demyelination was suppressed in CNS tissue and that lymphocyte infiltration was notably reduced. We conclude that the death receptors Fas and TNF-R1 are major initiators of ODC apoptosis in EAE. Although only moderate reduction of lymphocyte infiltration into CNS tissue was observed, the absence of these receptors appears to confer protection from demyelination and development of clinical disease.
authors.affiliation: Laboratory for Molecular Immunology, Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hövelmeyer
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.forename: Ksanthi
authors.initials: K
authors.lastname: Kranidioti
authors.forename: George
authors.initials: G
authors.lastname: Kassiotis
authors.forename: Thorsten
authors.initials: T
authors.lastname: Buch
authors.forename: Friederike
authors.initials: F
authors.lastname: Frommer
authors.forename: Lennart
authors.initials: L
authors.lastname: von Hoch
authors.forename: Dana
authors.initials: D
authors.lastname: Kramer
authors.forename: Liliana
authors.initials: L
authors.lastname: Minichiello
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
mesh_terms: D000818:Animals; D017209:Apoptosis; D003711:Demyelinating Diseases; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000473:pathology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D007376:Interleukin-2; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor; D007371:Interferon-gamma