Studies on the cytokine network in multiple sclerosis

Abstract: Multiple sclerosis (MS) is considered to be an inflammatory immune-mediated disease of the central nervous system (CNS), the aetiology of which remains enigmatic. Cytokines produced by infiltrating inflammatory cells and resident cells in the brain are proposed to play a major role in directing and regulating the immune response, as well as mediating tissue damage. In an attempt to further understand the role of cytokines in MS, in situ hybridisation with radiolabeled synthetic oligonucleotide probes was employed. mRNA expression for a number of pro- and antiinflammatory cytokines was determined in blood and cerebrospinal fluid (CSF) mononuclear cells (MNC) in patients with MS and control individuals. Elevated numbers of CSF MNC expressing mRNA for interleukin-12 (IL-12), IL-15, IL-17 and perforin were observed in MS patients compared to healthy individuals. The presence of cytokine mRNA expressing cells in the CSF was not specific for MS, since also patients with acute aseptic meningo-encephalitis had high numbers of MNC expressing IL-12 and perforin in the CSF. No differences in numbers of cytokine mRNA expressing CSF MNC could be detected when comparing optic neuritis patients with a low versus a high risk for future MS development. An association between perforin mRNA expressing MNC in CSF and disease activity as measured by gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) was observed in patients with MS, suggesting that perforin may be involved in blood-brain barrier disruption in MS. In-vitro treatment of blood MNC with interferon-ß-1b (IFN-ß-1b) reduced myelin antigen-induced expression of IFN-[gamma] tumor necrosis factor-[alpha], perforin and IL-4 mRNA, while the expression of transforming growth factor-ß and IL-6 mRNA was not affected. Suppression of proinflammatory cytokines may be one of the mechanisms behind the beneficial effects of IFN-ß-1b in MS. The occurrence of autoantibodies during IFN-ß treatment in MS was also assessed. Binding and neutralising anti-IFN-ß antibodies were detected using an immunoassay and a cytopathic virus inhibition assay. Antinuclear antibodies (ANA), thyroid microsomal antibodies (TIVIA), smooth muscle antibodies (SMA) and a number of heterophilic antibodies were analysed using standard immunofluorescence. Both IFN-ß-1a and (IFN-ß-1b) treatment resulted in the development of binding and neutralising anti-IFN-ß antibodies in patients with MS. A higher frequency of antibody positive patients was observed during IFN-ß-1b treatment compared to treatment with IFN- ß-1a. In spite of high concentrations of binding anti-IFN-ß-1b antibodies in plasma, only one of 17 patients treated with (IFN-ß-1b) had such antibodies in CSF No effect of (IFN-ß- 1b) treatment on the prevalence of ANA, TMA, SMA or a number of heterophilic autoantibodies could be detected. In conclusion, both pro- and antiinflammatory cytokines were upregulated in the CSF in MS. Also patients with other inflammatory diseases in the CNS had increased production of several cytokines in the CSF, indicating that cytokine responses probably are more related to the CNS inflammation per se than to a specific process causing MS. Individual cytokines seem, however, to be regulated independently from each other, and thus the net balance of cytokines most probably influences the course of MS.