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 < 0.007). IFN-ß injections in SPMS decreased expression of pro-inflammatory genes and increased anti-inflammatory, anti-oxidant metallothionein genes. Pro-inflammatory and anti-inflammatory protein levels were balanced in HC, disrupted in RRMS, and intermediate in SPMS. Interpretation: Aberrant gene expression seen in RRMS wanes in SPMS, paralleling fewer clinical exacerbations and diminished therapeutic responses. Novel biomarkers for SPMS suggest new targets to correct subnormal immune regulation and brain repair in this neurodegenerative disease. 59 blood and serum samples were collected from 49 subjects, including 10 healthy controls (HC), 9 untreated clinically stable RRMS, and 20 untreated SPMS (10 slowly progressive, 10 rapidly progressive). 10 long-term subcutaneous IFN-ß-1a-treated SPMS (Rebif, 44 mcg thrice weekly) provided paired samples after > 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