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.
Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death
Address correspondence to Jack P. Antel, M.D., Montreal Neurological Institute, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
Supported in part by the Medical Research Council (Canada) ( J.P. Antel and S.D. D'Souza), Health and Human Services, NIH grants NS 08952 and NS 11920 (C.S. Raine), National Multiple Sclerosis Society grant RG 1001-I-9 (C.S. Raine), and a fellowship from the Italian Multiple Sclerosis Society (B. Bonetti).
1Abbreviations used in this paper: BCIP, brom-chlor-indolyl phosphate; CNPase, cyclic nucleotide phosphodiesterase; CNS, central nervous system; DAB, 3,3′-diaminobenzidine; fasL, fas ligand; GalC, galactocerebroside; GFAP, glial fibrillary acidic protein; hsp, heat shock protein; LDH, lactate dehydrogenase; MS, multiple sclerosis; NBT, nitroblue tetrazolium; OL, oligodendrocyte; OND, other neurological diseases; PI, propidium iodide; TdT, terminal transferase; TUNEL, TdT-mediated dUTP-biotin nick-end-labeling; UTP, uridine triphosphate.
Sameer D. D'Souza, Bruno Bonetti, Vijayabalan Balasingam, Neil R. Cashman, Philip A. Barker, Anthony B. Troutt, Cedric S. Raine, Jack P. Antel; Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death. J Exp Med 1 December 1996; 184 (6): 2361–2370. doi: https://doi.org/10.1084/jem.184.6.2361
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