Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis.
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.
Hövelmeyer
Nadine
N
Laboratory for Molecular Immunology, Institute for Genetics, University of Cologne, Cologne, Germany.
Hao
Zhenyue
Z
Kranidioti
Ksanthi
K
Kassiotis
George
G
Buch
Thorsten
T
Frommer
Friederike
F
von Hoch
Lennart
L
Kramer
Dana
D
Minichiello
Liliana
L
Kollias
George
G
Lassmann
Hans
H
Waisman
Ari
A
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*
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