A type i interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis

M. Comabella, J. D. Lünemann, J. Río, A. Sánchez, C. López, E. Julià, M. Fernández, L. Nonell, M. Camiña-Tato, F. Deisenhammer, E. Caballero, M. T. Tortola, M. Prinz, X. Montalban, R. Martin

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168 Citations (Scopus)

Abstract

The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-β in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-β for a minimum of 2 years and classified as responders and non-responders based on clinical criteria. A validation cohort of 30 multiple sclerosis patients was included in the study to replicate gene-expression findings. Before treatment, interferon-β responders and non-responders were characterized by differential expression of type I interferon-induced genes with overexpression of the type interferon-induced genes in non-responders. Upon treatment the expression of these genes remained unaltered in non-responders, but was strongly upregulated in responders. Functional experiments showed a selective increase in phosphorylated STAT1 levels and interferon receptor 1 expression in monocytes of non-responders at baseline. When dissecting this type I interferon signature further, interferon-β non-responders were characterized by increased monocyte type I interferon secretion upon innate immune stimuli via toll-like receptor 4, by increased endogenous production of type I interferon, and by an elevated activation status of myeloid dendritic cells. These findings indicate that perturbations of the type I interferon signalling pathway in monocytes are related to lack of response to interferon-β, and type I interferon-regulated genes may be used as response markers in interferon-β treatment.
Original languageEnglish
Pages (from-to)3353-3365
JournalBrain
Volume132
Issue number12
DOIs
Publication statusPublished - 1 Jan 2009

Keywords

  • Gene-expression signature
  • Interferon-beta
  • Monocytes
  • Multiple sclerosis

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