CELL-DEATH AND BIRTH IN MULTIPLE-SCLEROSIS BRAIN

The hallmark of the brain pathology in multiple sclerosis is the white matter plaque, characterized by myelin destruction and oligodendrocyt e loss. To examine the role that cell death plays in the development o f MS lesions, we used the in situ TUNEL technique, a method that sensi tively detects DNA fragmentation associated with death at the single c ell level. We found that patchy areas within acute MS lesions have mas sive numbers of inflammatory and glial cells undergoing cell death. Th e punched out areas of some long-standing chronic lesions also had lab eled glial cells showing that the attack was not a single event. Immun ocytochemical identification of the dying cells with glial specific ma rker co-labeling showed that 14-40% were the myelin-sustaining oligode ndroglial cell. Confocal microscopic evaluation of fluorescein-Iabeled TUNEL positive cells revealed nuclei with morphologic characteristics of apoptosis, and electrophoresed MS brain DNA produced a ladder char acteristic of apoptotic DNA cleavage confirming that substantial numbe rs of labeled cells, but not necessarily all, were dying by apoptotic mechanisms rather than cell necrosis. Companion studies using a marker for cell proliferation on MS lesions revealed that unexpectedly large populations of perivascular inflammatory cells and parenchymal glial cells had entered the cell proliferation cycle. These findings establi sh that two opposing glial cell responses - relentless cell death and coincident brisk cellular proliferation - are important features of MS pathology. In the end, however, glial cell loss prevails, and we susp ect apoptosis may be the critical death mechanism responsible for the depletion of myelin observed in this condition. (C) 1997 Elsevier Scie nce B.V.