Brain Advance Access published online on September 9, 2009
Brain, doi:10.1093/brain/awp228
A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis
1 Centre d'Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron (HUVH), Departament de Medicina de la Universitat Autònoma de Barcelona, 08035 Barcelona, Spain 2 Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, NY 10021-6399, USA 3 Departament d'Estadística, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain 4 Clinical Department of Neurology, Innsbruck Medical University, A-6020 Innsbruck, Austria 5 Servei de Microbiologia, HUVH, 08035 Barcelona, Spain 6 Institute of Neuropathology, Universität Freiburg, D-79106 Freiburg, Germany 7 Institució Catalana de Recerca i Estudis Avançats (icrea), 08035 Barcelona, Spain
Correspondence to:
Manuel Comabella, Unitat de Neuroimmunologia Clínica, CEM-Cat. Edif. EUI 2ª planta, Hospital Universitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain E-mail: mcomabel{at}ir.vhebron.net
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.
Key Words: multiple sclerosis; monocytes; gene-expression signature; interferon-beta
Abbreviations: EBV, Epstein Barr virus; HHV-6, human herpesvirus 6; IFN, interferon; IFNβ, interferon-beta; PBMC, peripheral blood mononuclear cells; TLR, toll-like receptor
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Received April 24, 2009. Revised June 30, 2009. Accepted July 23, 2009.
*These authors contributed equally to this work.
Present address: Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zürich, 8091 Zürich, Switzerland
Present address: Institute for Neuroimmunology and Clinical multiple sclerosis Research, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Eppendorf, 20251 Hamburg, Germany