AUGMENTED EXPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA AND LYMPHOTOXIN IN MONONUCLEAR-CELLS IN MULTIPLE-SCLEROSIS AND OPTIC NEURITIS

The involvement of the proinflammatory cytokines tumour necrosis facto r-alpha (TNF-alpha) and lymphotoxin (LT) in multiple sclerosis is sugg ested by the parallel occurrence of these proinflammatory cytokines in acute and chronic active multiple sclerosis brain lesions. We describ e the use of in situ hybridization with radiolabelled cDNA oligonucleo tide probes to detect and enumerate TNF-alpha and LT mRNA expressing m ononuclear cells without curture, and after culture in the presence of myelin basic protein (MBP), control antigens or without antigen. Comp ared with patients with aseptic meningo-encephalitis, non-inflammatory neurological diseases and healthy controls, the multiple sclerosis pa tients had elevated numbers of TNF-alpha and LT mRNA expressing mononu clear cells in blood when enumerated without previous culture, and als o after culture wish MBP. The MBP-induced upregulation of TNF-alpha an d LT was major histocompatibility complex (MHC) class II molecule depe ndent. dependent. Tumour necrosis factor-alpha mRNA expressing mononuc lear cells were further enriched in the multiple sclerosis patients' C SF. Positive correlations were observed in multiple sclerosis between TNF-alpha and LT mRNA expressing blood mononuclear cells, MBP-reactive TNF-alpha and LT mRNA expressing cells, and TNF-alpha and interferon- gamma (IFN-gamma) mRNA expressing mononuclear cells. Upregulation of T NF-alpha correlated positively with exacerbation, enhanced disability and the secondary progressive phase of multiple sclerosis, Patients wi th optic neuritis, in many instances representing very early multiple sclerosis, had TNF-alpha and LT positive blood mononuclear cells that were elevated to the same extent as patients with clinically definite multiple sclerosis. The findings support the hypothesis that TNF-alpha and LT play a harmful role in the development of multiple sclerosis a nd suggest that TNF-alpha could be useful as a disease activity marker in multiple sclerosis.