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

Area of Science:

• Neuroimmunology
• Molecular Medicine
• Genetics

Background:

• Multiple sclerosis (MS) involves central nervous system (CNS) autoimmune inflammation, demyelination, and neurodegeneration.
• Untreated MS patients show reduced p-Ser-STAT1 activation in PBMCs, leading to weak interferon (IFN) signaling and low IFN-stimulated gene (ISG) expression.
• IFN-β therapy is known to reduce MS exacerbations and improve gene expression in PBMCs.

Purpose of the Study:

• To investigate the short- and long-term effects of prolonged PEG-IFN-β therapy on IFN responses in MS patients.
• To determine how long IFN-stimulated gene expression persists during and after long-term therapy.
• To understand if IFN-β therapy induces a more IFN-responsive state and regulates MS immunity.

Main Methods:

• Paired comparisons of peripheral blood mononuclear cells (PBMCs) from MS patients treated with PEG-IFN-β for 1 and 7 months.
• Analysis of gene expression profiles to assess short- and long-term responses to in vivo IFN-β.
• Evaluation of gene half-lives and regulatory mechanisms of IFN signaling.

Main Results:

• Prolonged IFN-β therapy established a new immune setpoint with increased expression of antiviral, immune-modulating, anti-inflammatory, and neuroprotective ISGs.
• Expression of inflammatory and metabolic genes decreased, with some ISG half-lives doubling.
• Long-term induction of genes inhibiting IFN-β signaling was observed, indicating a regulatory state preventing overactivation.

Conclusions:

• Long-term IFN-β therapy shifts MS immune control from a subnormal IFN signaling state to a more responsive and regulated state.
• This enhanced IFN response and immune regulation persist for months, suggesting a lasting priming effect.
• IFN-β therapy fundamentally alters the immune landscape in MS, promoting neuroprotection and reducing inflammation.