AbstractThree weeks after the administration of intravenous methylprednisolone therapy, a 42-year-old female patient suffering from relapsing-remitting multiple sclerosis (RR-MS) presented with a profound elevation of liver transaminases (GOT 485 U/l, GPT 1082 U/l, glutamyl transpeptidase 170 U/l). Liver biopsy revealed a profound, still active hepatitis with portal lymphocytic infiltration and fibrosis. Most likely, existing acute hepatitis was of autoimmune origin and emerged from an immune rebound phenomenon after immunosuppressive therapy.

Objective: Members of the tumor necrosis factor (TNF) receptor superfamily play a major role in the pathogenesis of multiple sclerosis. To elucidate the role of TNF receptors, in 53 relapsing-remitting multiple sclerosis patients, we measured the TNF receptor 1 and receptor 2 (TNF-R1 and TNF-R2) mRNA levels in peripheral blood leukocytes in natural history (n = 27) and during administration of interferon (IFN) β-1a (n = 26). Methods: Every 3 months for the duration of 1 year peripheral blood leukocytes were investigated by quantitative reverse transcription polymerase chain reaction. Every 6 months, MRI scans of the brain were analyzed semiquantitatively. Results: At baseline, clinical expanded disability status scale score and TNF-R1 mRNA level were correlated. In the therapy group, the difference between T2 lesion load at baseline and after 12 months correlated negatively with the difference between TNF-R1 mRNA level at baseline and after 12 months. Subcutaneously applied IFN β increased the amount of TNF-R1 mRNA, but partly decreased the amount of TNF-R2 mRNA in clinically and subclinically defined responders to therapy after 1 year compared to baseline. Conclusion: This result might support the notion that due to different signal transduction properties of both receptors in the natural course of multiple sclerosis, TNF-α signaling in leukocytes via TNF-R1 might be beneficial, but detrimental via proinflammatory TNF-R2: part of the therapeutic efficacy of current first-line standard therapy with IFN might be due to the modulation of signal transduction pathways.

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