A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis
A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis
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DOI：
10.1093/brain/awp228
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发表时间：
2009-12-01
期刊：
影响因子：
14.5
通讯作者：
Martin, R.
中科院分区：
文献类型：
--
作者：
Comabella, M.;Luenemann, J. D.;Martin, R.
β-干扰素在多发性硬化症中的作用是适度的，许多患者对治疗没有反应。迄今为止，没有一个生物标志物与多发性硬化症患者对干扰素β的反应性可靠相关。在本研究中，对47例多发性硬化症患者的外周血单核细胞进行了全基因组表达谱分析，这些患者接受了至少2年的β-干扰素治疗，并根据临床标准分为应答者和非应答者。研究中包括了30名多发性硬化症患者的验证队列，以复制基因表达结果。在治疗前，干扰素-β应答者和无应答者的特征在于I型干扰素诱导基因的差异表达与无应答者中I型干扰素诱导基因的过表达。治疗后，这些基因的表达在无应答者中保持不变，但在应答者中强烈上调。功能实验显示，在基线时，无应答者单核细胞中磷酸化STAT 1水平和干扰素受体1表达选择性增加。当进一步剖析这种I型干扰素特征时，干扰素-β无应答者的特征在于通过toll样受体4的先天免疫刺激后单核细胞I型干扰素分泌增加，I型干扰素的内源性产生增加，以及髓样树突细胞的活化状态升高。这些研究结果表明，干扰素信号通路在单核细胞中的干扰素干扰素干扰素β缺乏反应，和I型干扰素调节基因可用作干扰素β治疗的反应标志物。
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.