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Multiple sclerosis is considered to be an autoimmune disorder affecting the CNS, and several lines of evidence have supported the role of immunological mechanisms in its pathogenesis.1 2The clinical finding that viral infections are often associated with or followed by acute multiple sclerosis relapses also suggests that an activation of the peripheral immune compartment may contribute to an acceleration of disease progression. Interferons (IFNs)—known as cytokines with antiviral, antiproliferative and immunomodulatory properties—have become part of the treatment of the disease as IFNβ-1b has been shown to alter the natural course of relapsing-remitting multiple sclerosis.3 The interferon system forms an integral part of the defence system against infections. In response to viral stimulation, whole blood leucocytes of healthy people mainly produce IFN-α and a small proportion of IFN-β. IFN-α and β are structurally and functionally related and classified as type I interferons.4 However, studies on the role of endogenous type I interferons in the disease process of multiple sclerosis are rare and the results have been largely inconclusive, so that the exact mechanisms by which IFNβ-1b lessens the frequency of attacks of multiple sclerosis still remain open to speculation.5
We investigated the ability of whole-blood leucocytes of 15 patients with multiple sclerosis to produce endogenous IFN-α and β in response to stimulation with Newcastle disease virus. The whole-blood assay is an effective method for analysing the production of interferons and provides an appropriate model of the in vivo situation.6 Briefly, 100 μl heparinised blood were mixed with culture medium at a ratio of 1:10 and stimulated with Newcastle disease virus in a final concentration of 0.8 haemagglutinating units/ml. Unstimulated assays served as controls. Concentrations of IFN-α and β in the supernatants of cell cultures were determined after 48 hours of stimulation by means of quantitative enzyme linked immunosorbent assay (ELISA). All patients had clinically definite multiple sclerosis of the relapsing-remitting subtype and had been in remission for at least three months. None of the patients had received immunosuppressive treatment or steroids during the three months before blood sampling and plasma concentrations of C reactive protein were normal in all patients. As a control group, we examined 20 age matched, healthy blood donors.
We found that patients with multiple sclerosis produced significantly lower amounts of IFN-α and β than the control group (figure). There was no spontaneous release of IFNs in either group. Previous studies on cytokine production in patients with multiple sclerosis have mainly focused on alterations during acute attacks and disclosed an upregulation of proinflammatory cytokines—for example, TNF-α—and an impaired production of immunosuppressive cytokines—for example, TGF-β—in active disease.2 7 Our findings imply a deficit in the ability to produce type I interferons in patients with stable multiple sclerosis, which may be a predisposing factor for susceptibility to disease. The finding seems to be specific to multiple sclerosis, as type I interferon responsiveness has been shown to be normal in patients with idiopathic Parkinson′s disease and in schizophrenic patients by our laboratory recently.8 9 The mechanisms by which treatment with IFNβ-1b exerts its positive effects on the disease process might be explained by substitution of type-I interferon in patients with multiple sclerosis. Certainly, many different explanations may also be found.
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