Long-Term IFN-β Therapy Enhances and Prolongs IFN Responses in Multiple Sclerosis

Multiple sclerosis (MS) is a central nervous system (CNS) disease with autoimmune inflammation, demyelination, and neurodegeneration. Untreated MS patients exhibit subnormal activation of the p-Ser-STAT1 transcription factor in peripheral blood mononuclear cells (PBMCs), causing weak interferon (IFN) signaling and low expression of some IFN-stimulated genes (ISGs). IFN-β therapy reduces MS exacerbations, delays progression, and largely corrects abnormal gene expression in PBMC. We hypothesize that long-term IFN-β therapy improves weak IFN responses and regulates MS immunity through a priming effect and induction of a more IFN-responsive state. The duration and strength of IFN-stimulated gene expression during prolonged therapy and their diminution after discontinuation are unknown. Using paired comparisons of 1- and 7-month PEG-IFN-β-treated MS patients’ PBMCs, we investigated short- and long-term responses to in vivo IFN-β. Prolonged therapy created a new IFN setpoint with elevated expression of antiviral, immune, anti-inflammatory, and neuroprotective ISG while decreasing inflammatory and metabolic gene expression, often doubling their half-life. Genes that inhibit IFN-β signaling also showed long-term induction, reflecting a regulatory state that prevents overactivation. Strong IFN responses during long-term therapy of MS reflect a shift from subnormal IFN signaling and dysregulated immune control to a more responsive state that persists for months.