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

被引：163

作者：

Comabella, M. ^{[1
]}

Luenemann, J. D. ^{[2
]}

Rio, J. ^{[1
]}

Sanchez, A. ^{[3
]}

Lopez, C. ^{[1
]}

Julia, E. ^{[1
]}

Fernandez, M. ^{[1
]}

Nonell, L. ^{[1
]}

Camina-Tato, M. ^{[1
]}

Deisenhammer, F. ^{[4
]}

Caballero, E. ^{[5
]}

Tortola, M. T. ^{[5
]}

Prinz, M. ^{[6
]}

Montalban, X. ^{[1
]}

Martin, R. ^{[7
]}

机构：

[1] Univ Autonoma Barcelona, Unitat Neuroimmunol Clin, CEM Cat,Hosp Univ Vall Hebron, Ctr Esclerosi Multiple Catalunya,Dept Med, Barcelona 08035, Spain

[2] Rockefeller Univ, Lab Viral Immunobiol, Christopher H Browne Ctr Immunol & Immune Dis, New York, NY 10021 USA

[3] Univ Barcelona, Fac Biol, Dept Estadist, E-08028 Barcelona, Spain

[4] Innsbruck Med Univ, Dept Clin Neurol, A-6020 Innsbruck, Austria

[5] HUVH, Microbiol Serv, Barcelona 08035, Spain

[6] Univ Freiburg, Inst Neuropathol, D-79106 Freiburg, Germany

[7] Icrea, Barcelona 08035, Spain

来源：

BRAIN | 2009年 / 132卷

关键词：

multiple sclerosis; monocytes; gene-expression signature; interferon-beta; SYSTEMIC-LUPUS-ERYTHEMATOSUS; PERIPHERAL-BLOOD CELLS; TIME QUANTITATIVE PCR; DENDRITIC CELLS; GENE-EXPRESSION; IFN-BETA; IMMUNE-RESPONSE; VIRAL-INFECTION; DOUBLE-BLIND; T-CELLS;

D O I：

10.1093/brain/awp228

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：3353 / 3365

页数：13

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