Interferon-β corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection

Background: In multiple sclerosis (MS), immune up-regulation is coupled to subnormal immune response to interferon-β (IFN-β) and low serum IFN-β levels. The relationship between the defect in IFN signalling and acute and long-term effects of IFN-β on gene expression in MS is inadequately understood. Methods: We profiled IFN-β-induced transcriptome shifts, using high-resolution microarrays on 227 mononuclear cell samples from IFN-β-treated MS Complete Responders (CR) stable for five years, and stable and active Partial Responders (PR), stable and active untreated MS, and healthy controls. Findings: IFN-β injection induced short-term changes in 1,200 genes compared to baseline expression after 4-day IFN washout. Pre-injection after washout, and in response to IFN-β injections, PR more frequently had abnormal gene expression than CR. Surprisingly, short-term IFN-β induced little shift in Th1/Th17/Th2 gene expression, but up-regulated immune-inhibitory genes (ILT, IDO1, PD-L1). Expression of 8,800 genes was dysregulated n therapy-naïve compared to IFN-β-treated patients. These long-term changes in protein-coding and long non-coding RNAs affect immunity, synaptic transmission, and CNS cell survival, and correct the disordered therapy-naïve transcriptome to near-normal. In keeping with its impact on clinical course and brain repair in MS, long-term IFN-β treatment reversed the overexpression of proinflammatory and MMP genes, while enhancing genes involved in the oligodendroglia-protective integrated stress response, neuroprotection, and immunoregulation. In the rectified long-term signature, 277 transcripts differed between stable PR and CR patients. 227 samples,from 54 subjects. 27 relapsing/remitting MS (RRMS) on IFN-β therapy for 8·14 ± 0·86 years. 12 were Complete Responders to IFN-β therapy, exacerbation-free >6 months before sampling. 15 Partial R patients were stable for >6 months, and were also followed for 5 years. PR were also sampled during an exacerbation. Therapy-naïve included 10 with stable RRMS and 9 RRMS during exacerbations. Ther were age- and sex-macthed with 8 healthy controls.