Multiple sclerosis: Fas signaling in oligodendrocyte cell death

Fas is a cell surface receptor that transduces cell death signals when cross-linked by agonist antibodies or by fas ligand. In this study, we examined the potential of fas to contribute to oligodendrocyte (OL) injury and demyelination as they occur in the human demyelinating disease multiple scleros...

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Bibliographic Details
Published in:The Journal of experimental medicine 1996-12, Vol.184 (6), p.2361-2370
Main Authors: D'Souza, S D, Bonetti, B, Balasingam, V, Cashman, N R, Barker, P A, Troutt, A B, Raine, C S, Antel, J P
Format: Article
Language:English
Subjects:
Adult
Cell Death
Cells, Cultured
Central Nervous System - cytology
Central Nervous System - pathology
Central Nervous System - physiopathology
fas Receptor - biosynthesis
fas Receptor - physiology
Humans
Immunohistochemistry
Middle Aged
Multiple Sclerosis - immunology
Multiple Sclerosis - pathology
Multiple Sclerosis - physiopathology
Neuroglia - cytology
Neuroglia - pathology
Neuroglia - physiology
Oligodendroglia - cytology
Oligodendroglia - pathology
Oligodendroglia - physiology
Reference Values
Signal Transduction
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Summary:Fas is a cell surface receptor that transduces cell death signals when cross-linked by agonist antibodies or by fas ligand. In this study, we examined the potential of fas to contribute to oligodendrocyte (OL) injury and demyelination as they occur in the human demyelinating disease multiple sclerosis (MS). Immunohistochemical study of central nervous system (CNS) tissue from MS subjects demonstrated elevated fas expression on OLs in chronic active and chronic silent MS lesions compared with OLs in control tissue from subjects with or without other neurologic diseases. In such lesions, microglia and infiltrating lymphocytes displayed intense immunoreactivity to fas ligand. In dissociated glial cell cultures prepared from human adult CNS tissue, fas expression was restricted to OLs. Fas ligation with the anti-fas monoclonal antibody M3 or with the fas-ligand induced rapid OL cell membrane lysis, assessed by LDH release and trypan blue uptake and subsequent cell death. In contrast to the activity of fas in other cellular systems, dying OLs did not exhibit evidence of apoptosis, assessed morphologically and by terminal transferase-mediated d-uridine triphosphate-biotin nick-end-labeling staining for DNA fragmentation. Other stimuli such as C2-ceramide were capable of inducing rapid apoptosis in OLs. Antibodies directed at other surface molecules expressed on OLs or the M33 non-activating anti-fas monoclonal antibody did not induce cytolysis of OLs. Our results suggest that fas-mediated signaling might contribute in a novel cytolytic manner to immune-mediated OL injury in MS.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.184.6.2361