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

ABSTRACT

BACKGROUND: In multiple sclerosis (MS), immune up-regulation is coupled to subnormal immune response to interferon-ß (IFN-ß) and low serum IFN-ß levels. The relationship between the defect in IFN signalling and acute and long-term effects of IFN-ß on gene expression in MS is inadequately understood. METHODS: We profiled IFN-ß-induced transcriptome shifts, using high-resolution microarrays on 227 mononuclear cell samples from IFN-ß-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-ß 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-ß injections, PR more frequently had abnormal gene expression than CR. Surprisingly, short-term IFN-ß 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 in therapy-naïve compared to IFN-ß-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-ß 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. INTERPRETATION: IFN-ß had minimal short-term effects on Th1 and Th2 pathways, but long-term it corrected gene dysregulation and induced immunoregulatory and neuroprotective genes. These data offer new biomarkers for IFN-ß responsiveness. FUNDING: Unrestricted grants from the US National MS Society, NMSS RG#4509A, and Bayer Pharmaceuticals.