Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis

Abstract

Interferon beta (IFNβ) reduces disease burden in relapsing-remitting multiple sclerosis (MS) patients. In this study, IFNβ-1b-treated MS patient gene expression profiles and biological knowledgebases were integrated to study IFNβ's pleiotropic mechanisms of action. Genes involved in immune regulation, mitochondrial fatty acid metabolism and antioxidant activity were discovered. Plausible mediators of neuronal preservation included NRF2, downregulation of OLA1, an antioxidant suppressor, and the antioxidant gene ND6, implicated in optic neuropathy and MS-like lesions. Network analysis highlighted IKBKE, which likely has a role in both viral response and energy metabolism. A comparative analysis of therapy-naive MS- and IFNβ-associated gene expression suggests an IFNβ insufficiency in MS. We observed more gene expression changes in long-term treatment than during acute dosing. These distinct short- and long-term effects were driven by different transcription factors. Multi-gene biomarker signatures of IFNβ treatment effects were developed and subsequently confirmed in independent IFNβ-1b-treated MS studies, but not in glatiramer acetate-treated patients.

Immunomodulatory activity of interferon‐beta

“…Induction of TIMP-1, the main inhibitor of MMP-9, may also be a marker of response to interferon-beta 39. Differences in molecular signatures include upregulation of many genes related to immune regulation, but also into protective and antioxidant profiles in most treated patients 58. In parallel, an exaggerated molecular response to interferon-beta in a subset of patients with MS has been associated with a poor response to treatment 59.…”

Cutting Edge: Vitamin D Regulates Lipid Metabolism in Mycobacterium tuberculosis Infection

“…Statistical analysis was performed in R. One-sided and two-sided t-tests were performed to compare measurements of transcript levels between sample groups, and the resulting p-values calculated. To evaluate gene sets defined by Reactome [http://reactome.org/,2012-09-04], Gene Ontology [http://www.geneontology.org/, 2012-04-10], or by transcriptional modulators (16), each set was tested for extreme ranks of differential expression among all measured genes in each comparison by CERNO (Coincident Extreme Ranks in Numerical Observations), and multiple transcript measurements were combined as described (17). The Benjamini-Hochberg method was used to calculate false discovery rate (FDR).…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…As a consequence of the altered immune and redox homeostasis, HO-1 expression is reduced in peripheral blood mononuclear cells of MS patients and is downregulated during exacerbation of the disease (Fagone et al, 2013). Of note, gene expression profiling in interferon-b-treated patients identified NRF2 as a potential mediator of longterm antioxidant response and neuronal preservation (Croze et al, 2013).…”