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

EBioMedicine. 2019 Nov;49:269-283. doi: 10.1016/j.ebiom.2019.09.059. Epub 2019 Oct 21.

Abstract

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 in 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.

Interpretation: IFN-β 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-β responsiveness.

Funding: Unrestricted grants from the US National MS Society, NMSS RG#4509A, and Bayer Pharmaceuticals.

Keywords: Gene expression; ILT; Immune regulation; Interferon-beta; Multiple sclerosis; RNA microarray.

MeSH terms

  • Gene Expression Regulation / drug effects
  • Humans
  • Interferon-beta / pharmacology*
  • Middle Aged
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • Neuroprotection / drug effects
  • Neuroprotection / genetics*
  • Open Reading Frames / genetics
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Time Factors
  • Transcriptome / genetics

Substances

  • RNA, Long Noncoding
  • Interferon-beta