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

作者：Comabella M^*; Luenemann J D; Rio J; Sanchez A; Lopez C; Julia E; Fernandez M; Nonell L; Camina Tato M; Deisenhammer F; Caballero E; Tortola M T; Prinz M; Montalban X; Martin R

来源：Brain, 2009, 132(12): 3353-3365.

DOI：10.1093/brain/awp228

• multiple sclerosis
• monocytes
• gene-expression signature
• interferon-beta

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.

• 出版日期2009-12