title: A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis.
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-beta 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-beta 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-beta 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-beta 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-beta, and type I interferon-regulated genes may be used as response markers in interferon-beta treatment.
authors.affiliation: Unitat de Neuroimmunologia Clínica, CEM-Cat. Edif. EUI 2 feminine planta, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain. mcomabel@ir.vhebron.net
authors.forename: M
authors.initials: M
authors.lastname: Comabella
authors.forename: J D
authors.initials: JD
authors.lastname: Lünemann
authors.forename: J
authors.initials: J
authors.lastname: Río
authors.forename: A
authors.initials: A
authors.lastname: Sánchez
authors.forename: C
authors.initials: C
authors.lastname: López
authors.forename: E
authors.initials: E
authors.lastname: Julià
authors.forename: M
authors.initials: M
authors.lastname: Fernández
authors.forename: L
authors.initials: L
authors.lastname: Nonell
authors.forename: M
authors.initials: M
authors.lastname: Camiña-Tato
authors.forename: F
authors.initials: F
authors.lastname: Deisenhammer
authors.forename: E
authors.initials: E
authors.lastname: Caballero
authors.forename: M T
authors.initials: MT
authors.lastname: Tortola
authors.forename: M
authors.initials: M
authors.lastname: Prinz
authors.forename: X
authors.initials: X
authors.lastname: Montalban
authors.forename: R
authors.initials: R
authors.lastname: Martin
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000032:analysis / Q000378:metabolism*; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D011446:Prospective Studies; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D015415:Biomarkers; D007370:Interferon Type I; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016899:Interferon-beta