Cell-specific type I IFN signatures in autoimmunity and viral infection: what makes the difference?
Cell-specific type I IFN signatures in autoimmunity and viral infection: what makes the difference?
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DOI：
10.1371/journal.pone.0083776
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Grützkau A
中科院分区：
文献类型：
--
作者：
Kyogoku C;Smiljanovic B;Grün JR;Biesen R;Schulte-Wrede U;Häupl T;Hiepe F;Alexander T;Radbruch A;Grützkau A
外周血单个核细胞（PBMCs）基因表达谱显示，I型干扰素（IFN）在系统性红斑狼疮（SLE）的发病机制中起着至关重要的作用。然而，目前还不清楚特定的白细胞亚群如何有助于PBMCs和全血样品的总体I型IFN签名。此外，迄今为止，尚未进行详细的分析，描述在病毒感染后观察到的IFN签名在自身免疫性疾病中的差异。因此，在本研究中，外周T辅助细胞（CD 4+）和单核细胞亚群的转录反应，（CD 16 −炎性和CD 16+驻留单核细胞），分离自SLE患者，接种黄热病疫苗YFV的健康献血者（ND）-17 D和未处理的对照组通过整体基因表达谱进行了比较。在SLE中也发现差异调节，尽管倍数变化值明显较低。除了这种常见的IFN信号外，在狼疮患者的CD 4 + T细胞和单核细胞中检测到致病性IFN相关基因信号。IL-10、IL-9和IL-15介导的JAK/STAT信号转导被证明参与SLE中观察到的IFN应答的病理放大。I型干扰素签名鉴定成功地应用于监测干扰素反应的PBMC的一个独立的队列的SLE患者和病毒感染的个人。此外，这些细胞类型特异性基因签名允许独立于其异源细胞组成的PBMC的正确分类。总之，我们的数据首次表明，单核细胞和CD 4细胞是敏感的生物传感器，以监测I型干扰素的响应签名在自身免疫和病毒感染，以及这些transriptional响应是如何调制的细胞和疾病特异性的方式。
Gene expression profiling of peripheral blood mononuclear cells (PBMCs) has revealed a crucial role for type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE). However, it is unclear how particular leucocyte subsets contribute to the overall type I IFN signature of PBMCs and whole blood samples.Furthermore, a detailed analysis describing the differences in the IFN signature in autoimmune diseases from that observed after viral infection has not been performed to date. Therefore, in this study, the transcriptional responses in peripheral T helper cells (CD4+) and monocyte subsets (CD16− inflammatory and CD16+ resident monocytes) isolated from patients with SLE, healthy donors (ND) immunised with the yellow fever vaccine YFV-17Dand untreated controls were compared by global gene expression profiling.It was striking that all of the transcripts that were regulated in response to viral exposure were also found to be differentially regulated in SLE, albeit with markedly lower fold-change values. In addition to this common IFN signature, a pathogenic IFN-associated gene signature was detected in the CD4+ T cells and monocytes from the lupus patients. IL-10, IL-9 and IL-15-mediated JAK/STAT signalling was shown to be involved in the pathological amplification of IFN responses observed in SLE. Type I IFN signatures identified were successfully applied for the monitoring of interferon responses in PBMCs of an independent cohort of SLE patients and virus-infected individuals. Moreover, these cell-type specific gene signatures allowed a correct classification of PBMCs independent from their heterogenic cellular composition. In conclusion, our data show for the first time that monocytes and CD4 cells are sensitive biosensors to monitor type I interferon response signatures in autoimmunity and viral infection and how these transriptional responses are modulated in a cell- and disease-specific manner.
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