MULTIPLE-SCLEROSIS - EXPRESSION OF MOLECULES OF THE TUMOR-NECROSIS-FACTOR LIGAND AND RECEPTOR FAMILIES IN RELATIONSHIP TO THE DEMYELINATED PLAQUE

The molecules that comprise the tumor necrosis factor ligand and recep tor (TNF-L and TNF-R) families play important roles in tissue homeosta sis and in multiple sclerosis (MS). For example levels of the TNF liga nd (TNF alpha; cachectin) correlate with disease progression and lymph otoxin (LT, TNF beta) has been localized in MS lesions. Members of the TNF-R family are typical signal sensors which upon binding with ligan d 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 o f TNF, LT alpha (the soluble form of LT), LT beta (the beta chain of L T 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 immunohi stochemistry for protein and by RT-PCR for mRNA. in addition, the TUNE L technique for DNA fragmentation was applied to detect apoptosis. The results have shown that contrarily to predictions, oligodendrocytes a round active MS lesions frequently expressed TNF-R molecules belonging to the apoptotic cascade. However, these cells did not undergo apopto sis, as judged by TUNEL. On the other hand, lymphocytes (and a few mic roglial cells) in the same tissue displayed apoptosis. Microglial cell s were the major effector cells in the CNS and expressed TNF, LT alpha and FasL. LT beta expression was seen on astrocytes and oligodendrocy tes, and LT beta-R on astrocytes. We conclude that TNF-L and TNF-R mol ecules are extensively expressed in MS, that their expression occurs a t high levels but is not specific for MS, and that oligodendrocytes ar e depleted by a cytolytic mechanism, not by apoptosis.