Augmented expression of tumour necrosis factor-α and lymphotoxin in mononuclear cells in multiple sclerosis and optic neuritis

Abstract

The involvement of proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT) in multiple sclerosis is suggested by the parallel occurrence of these proinflammatory cytokines in acute and chronic active multiple sclerosis brain lesions. We describe the use of in situ hybridization with radiolabelled cDNA oligonucleotide probes to detect and enumerate TNF-alpha and LT mRNA expressing mononuclear cells without culture, and after culture in the presence of myelin basic protein (MBP), control antigens or without antigen. Compared with patients with aseptic meningo-encephalitis, non-inflammatory neurological diseases and healthy controls, the multiple sclerosis patients had elevated numbers of TNF-alpha and LT mRNA expressing mononuclear cells in blood when enumerated without previous culture, and also after culture with MBP. The MBP-induced upregulation of TNF-alpha and LT was major histocompatibility complex (MHC) class II molecule dependent. Tumour necrosis factor-alpha mRNA expressing mononuclear cells were further enriched in the multiple sclerosis patients' CSF. 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 (INF-gamma) mRNA expressing mononuclear cells. Upregulation of TNF-alpha correlated positively with exacerbation, enhanced disability and the secondary progressive phase of multiple sclerosis. Patients with 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 and suggest that TNF-alpha could be useful as a disease activity marker in multiple sclerosis.

Review: cytokines and the pathogenesis of multiple sclerosis

“…Thereby, LT-a may facilitate the recruitment of activated autoantigenreactive T lymphocytes into the CNS. A positive correlation was observed between LT-a and TNF-a mRNAexpressing blood MNCs in MS (Navikas et al, 1996a), suggesting that LT-a may act together with TNF-a and other proinflammatory cytokines within the cytokine network, contributing to the perpetuation of an immunopathological process. A disease-promoting role of TNFa and LT-a is further supported by studies in EAE.…”

“…TNF-a mRNA-expressing MNCs were elevated in blood and even more in CSF in MS and in monosymptomatic optic neuritis (ON; Link et al , 1995;Navikas et al, 1996a). Numbers of MBP-reactive TNF-a mRNApositive cells were also elevated.…”

“…For example, TNF-a may synergize with IFN-y to up-regulate expression of MHC class I1 and adhesion molecules on macrophages and other accessory cells (Vassalli, 1992). A positive correlation was observed between numbers of TNF-a and IFN-y mRNA-expressing blood MNCs in MS patients (Navikas et al, 1996a). It is possible that proinflammatory cytokines, including TNF-a and IFN-y, may exert and potentiate their effects within a complex cytokine network.…”

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

“…IL-6 has been shown to stimulate T cell proliferation in vitro (51). TNF-␤ (LTA) is a member of the tumor necrosis factor family, shares its receptor with both TNF receptor-1 and -2, and induces its own expression in BV-2 microglial cells and macrophages to coordinate lymphocyte migration (52)(53)(54)(55).…”

Effects of Interferon β-1a and Interferon β-1b Monotherapies on Selected Serum Cytokines and Nitrite Levels in Patients with Relapsing-Remitting Multiple Sclerosis: A 3-Year Longitudinal Study

“…Among these cytokines, a dominant role in MS pathology is attributed to the TNFα, interleukin (IL)-6 and IFNγ, the accumulation of which is associated with MS symptoms [14,15]. Moreover, levels of TNFα and IFNγ in cerebrospinal fluid (CSF) and TNFα mRNA expression in peripheral blood mononuclear cells of MS patients were shown to correlate positively with disease activity and severity [16,17,18]. The importance of TNFα in MS was also suggested by its myelinotoxicity in cultures of mouse spinal cord tissue [19], and by partial suppression of demyelination by a monoclonal anti-TNFα antibody [20].…”