OLIGODENDROCYTE APOPTOSIS AND PRIMARY DEMYELINATION INDUCED BY LOCAL TNF P55TNF RECEPTOR SIGNALING IN THE CENTRAL-NERVOUS-SYSTEM OF TRANSGENIC MICE - MODELS FOR MULTIPLE-SCLEROSIS WITH PRIMARY OLIGODENDROGLIOPATHY/

The scientific dogma that multiple sclerosis (MS) is a disease caused by a single pathogenic mechanism has been challenged recently by the h eterogeneity observed in MS lesions and the realization that not all p atterns of demyelination can be modeled by auto-immune-triggered mecha nisms. To evaluate the contribution of local tumor necrosis factor (TN F) ligand/ receptor signaling pathways to MS immunopathogenesis we hav e analyzed disease pathology in central nervous system-expressing TNF transgenic mice, with or without p55 or p75TNF receptors, using combin ed in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling and cell identification techniques, Vile demonstrate that local production of TNF by central nervous system glia potently and selectively induces oligodendrocyte apoptosis and myelin vacuolati on in the context of an intact blood-brain barrier and absence of immu ne cell infiltration into the central nervous system parenchyma, Inter estingly, primary demyelination then develops in a classical manner in the presence of large numbers of recruited phagocytic macrophages, po ssibly the result of concomitant pro-inflammatory effects of TNF in th e central nervous system, and lesions progress into acute or chronic M S-type plaques with axonal damage, focal blood-brain barrier disruptio n, and considerable oligodendrocyte loss. Both the cytotoxic and infla mmatory effects of TNF were abrogated in mice genetically deficient fo r the p55TNF receptor demonstrating a dominant role for p55TNF recepto r-signaling pathways in TNF-mediated pathology, These results demonstr ate that aberrant local TNF/p55TNF receptor signaling in the central n ervous system can have a potentially major role ia the aetiopathogenes is of MS demyelination, particularly in MS subtypes in which oligodend rocyte death is a primary pathological feature, and provide new models for studying the basic mechanisms underlying oligodendrocyte and myel in loss.