The molecules that comprise the tumor necrosis factor ligand and receptor (TNF-L and TNF-R) families play important roles in tissue homeostasis and in multiple sclerosis (MS). For example, levels of the TNF ligand (TNF alpha; cachectin) correlate with disease progression and lymphotoxin (LT, TNF beta) has been localized in MS lesions. Members of the TNF-R family are typical signal sensors which upon binding with ligand aggregate and recruit signal transducers. To date, no TNF-R molecules have been reported in MS although TNF-RI and RII have been localized to oligodendrocytes in culture. In the present study, the expression of TNF, LT alpha (the soluble form of LT), LT beta (the beta chain of LT alpha beta, the membrane-bound form of LT), TNF-RI, TNF-RII, LT beta-R, FasL, and Fas receptor in MS lesions has been examined by immunohistochemistry for protein and by RT-PCR for mRNA. In addition, the TUNEL technique for DNA fragmentation was applied to detect apoptosis. The results have shown that contrarily to predictions, oligodendrocytes around active MS lesions frequently expressed TNF-R molecules belonging to the apoptotic cascade. However, these cells did not undergo apoptosis, as judged by TUNEL. On the other hand, lymphocytes (and a few microglial cells) in the same tissue displayed apoptosis. Microglial cells were the major effector cells in the CNS and expressed TNF, LT alpha and FasL. LT beta expression was seen on astrocytes and oligodendrocytes, and LT beta-R on astrocytes. We conclude that TNF-L and TNF-R molecules are extensively expressed in MS, that their expression occurs at high levels but is not specific for MS, and that oligodendrocytes are depleted by a cytolytic mechanism, not by apoptosis.