Novel Biomarkers and Interferon Signature in Secondary Progressive Multiple Sclerosis. Novel Biomarkers and Interferon Signature in Secondary Progressive Multiple Sclerosis

Transcriptome analysis of RNA samples from human PBMCs of IFN-beta-1a (Rebif) therapy in secondary progressive multiple sclerosis (SPMS) patients. Objective: Untreated multiple sclerosis is inflammatory, with decreased immune control and subnormal type I interferon (IFN) signaling. IFN-ß therapy corrects abnormal IFN-ß signaling, reduces inflammation on MRI, exacerbations, and disease worsening in relapsing-remitting MS (RRMS). For unclear reasons, secondary progressive MS (SPMS) exhibits waning attacks, relentless neurodegeneration, and diminished benefits of therapy. Methods: Peripheral blood mononuclear cells and serum were from 10 healthy controls (HC), 9 therapy-naive RRMS, 20 therapy-naïve SPMS, and 10 IFN-ß-treated SPMS patients after therapy washout and four hours after IFN-ß-1a injection. Global gene expression was assayed with sensitive RNA microarrays and multiplexed serum immune and neuroprotective protein assays. Results: Therapy-naive RRMS cells displayed 8,723 differentially expressed genes (DEG), compared to HC, vs. d only 3,936 DEG in therapy-naive SPMS. In SPMS, gene expression was subnormal in the WNT/ß-catenin pathway that suppresses inflammation and enhances blood-brain barrier integrity. Olfactory receptor (OR) genes, linked to lymphocyte migration, were overexpressed in RRMS (111 DEG), intermediate in SPMS (34 DEG) vs. HC, differentiating RRMS from SPMS (p 60-hour IFN washout (73.0 ± 8.9 hours; mean ± SEM) and four hours after IFN injection (4.07 ± 0.03 hours). Rapid, short-term RNA induction was studied 4 hours after injections, because injected IFN-beta levels peak at 30 minutes, followed by expression of many IFN-induced genes (ISG) within 2-3 hours. These include cytokines and also multiple subtypes of IFN-beta and IFN-alpha, based on serum IFN activity assays