Elevated type I interferon-like activity in a subset of multiple sclerosis patients: molecular basis and clinical relevance.
Elevated type I interferon-like activity in a subset of multiple sclerosis patients: molecular basis and clinical relevance.
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DOI：
10.1186/1742-2094-9-140
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发表时间：
2012-06-22
影响因子：
9.3
通讯作者：
Zettl UK
中科院分区：
文献类型：
--
作者：
Hundeshagen A;Hecker M;Paap BK;Angerstein C;Kandulski O;Fatum C;Hartmann C;Koczan D;Thiesen HJ;Zettl UK
一组多发性硬化症（MS）患者在开始ifn - β治疗前表现出内源性ifn样活性增加。这种现象的分子基础及其与预测个体治疗结果的相关性尚不完全清楚。我们研究了这些患者的表达模式，ifn样活性升高的预后价值，以及外源性ifn - β的基因调控作用。利用ifn - β治疗1个月前后获得的外周血单个核细胞，对61例MS患者进行微阵列基因表达谱分析。比较内源性ifn -样活性高（MX1high队列）和低（MX1low队列）患者诱导或激活ifn - β通路相关基因的表达水平。患者随访5年，并记录了扩展残疾状态量表（EDSS）的复发和进展情况。在治疗开始前，11名患者出现ifn刺激基因mRNA水平升高，这表明内源性ifn样活性相对较高（MX1high）。在这些患者中，病原体受体（如TLR7、RIG-I和IFIH1）和转录因子的表达也更强烈，这可能是由于IFN刺激基因因子3 （ISGF3，由STAT1、STAT2和IFN调节因子9组成的复合物）过度活跃。ifn - β治疗1个月后，许多通路基因的表达在MX1low患者中被显著诱导，但在MX1high患者中保持不变。在随访期间，两组患者的复发率和EDSS变化具有可比性，不同类型的ifn - β药物应用之间存在差异。治疗性ifn - β诱导参与ifn相关通路的几个基因的转录。在MS患者的一个亚组中，这些基因的表达在治疗开始前就已经增加，可能是由ISGF3的过度表达驱动的。内源性ifn样活性高和低的患者表现出相似的临床长期病程。不同的ifn - β药物制剂结果不同，值得进一步研究。
A subset of patients with multiple sclerosis (MS) shows an increased endogenous IFN-like activity before initiation of IFN-beta treatment. The molecular basis of this phenomenon and its relevance to predict individual therapy outcomes are not yet fully understood. We studied the expression patterns of these patients, the prognostic value of an elevated IFN-like activity, and the gene regulatory effects of exogenously administered IFN-beta. Microarray gene expression profiling was performed for 61 MS patients using peripheral blood mononuclear cells obtained before and after 1 month of IFN-beta therapy. Expression levels of genes involved in pathways either inducing or being activated by IFN-beta were compared between patients with high (MX1high cohort) and low (MX1low cohort) endogenous IFN-like activity. Patients were followed for 5 years and relapses as well as progression on the expanded disability status scale (EDSS) were documented. Before the start of therapy, 11 patients presented elevated mRNA levels of IFN-stimulated genes indicative of a relatively high endogenous IFN-like activity (MX1high). In these patients, pathogen receptors (for example, TLR7, RIG-I and IFIH1) and transcription factors were also expressed more strongly, which could be attributed to an overactivity of IFN-stimulated gene factor 3 (ISGF3, a complex formed by STAT1, STAT2 and IFN regulatory factor 9). After 1 month of IFN-beta therapy, the expression of many pathway genes was significantly induced in MX1low patients, but remained unaltered in MX1high patients. During follow-up, relapse rate and changes in EDSS were comparable between both patient groups, with differences seen between different types of IFN-beta drug application. Therapeutic IFN-beta induces the transcription of several genes involved in IFN-related pathways. In a subgroup of MS patients, the expression of these genes is already increased before therapy initiation, possibly driven by an overexpression of ISGF3. Patients with high and low endogenous IFN-like activity showed similar clinical long-term courses of disease. Different results were obtained for different IFN-beta drug preparations, and this merits further investigation.
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