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J. Exp. Med.
© The Rockefeller University Press
0022-1007/96/12/2361/10 $2.00
Volume 184 December 1996 2361-2370

Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death

By Sameer D. D'Souza,* Bruno Bonetti,par Vijayabalan Balasingam,* Neil R. Cashman,* Philip A. Barker,Dagger Anthony B. Troutt,§ Cedric S. Raine,par and Jack P. Antel*

From the * Neuroimmunology Unit and Dagger  Center for Neuronal Survival, Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada; § Immunex Corporation, Seattle, Washington 98101; and par  Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, New York 10461

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 nonactivating 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.


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