Development of a Validated Interferon Score Using NanoString Technology
Development of a Validated Interferon Score Using NanoString Technology
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DOI：
10.1089/jir.2017.0127
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发表时间：
2018-04-01
影响因子：
2.3
通讯作者：
Goldbach-Mansky, Raphaela
中科院分区：
文献类型：
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作者：
Kim, Hanna;de Jesus, Adriana A.;Goldbach-Mansky, Raphaela
干扰素（IFN）-应答基因（IRG）的慢性升高，在一个子集的患者全身免疫失调性疾病，包括孟德尔I型IFN介导的自身炎症性疾病和一些自身免疫性疾病表明过度的IFN信号在疾病的发病机制和治疗的目标的致病作用。我们开发了一种28-IFN应答基因评分系统，通过定制NanoString测定来定量推定IRGs的表达，以计算标准化或几何评分。基因靶点是在IFN介导的慢性非典型嗜中性皮肤病伴脂肪营养不良和体温升高（CANDLE）患者和接受第一剂聚乙二醇干扰素α-2a的慢性丙型肝炎成人患者中选择的。推定的靶基因在婴儿期发作的STING相关血管病变（SAVI）患者中得到验证，SAVI是一种由编码IFN基因（STING）的病毒传感器刺激物的TMEM 173中的功能获得性突变引起的单基因自身炎症性疾病，并且在具有单基因IL-1介导的自身炎症性疾病的临床活动性患者中具有低表达，脑源性多系统炎性疾病（NOMID）和健康对照。NanoString检测的评分计算快速，重现性高，检测内和检测间变异性低。这28个基因的IFN评分的效用可以探讨在诊断患者的假定干扰素病，并作为生物标志物，以评估疾病的活动，长期的结果，和治疗反应。
Chronic elevation of interferon (IFN)-response genes (IRG) in a subset of patients with systemic immune-dysregulatory diseases, including the Mendelian Type-I IFN-mediated autoinflammatory diseases and some autoimmune diseases suggest a causative role of excessive IFN signaling in the disease pathogenesis and as target for treatment. We developed a 28-IFN response gene scoring system to calculate either a standardized or geomean score by customizing a NanoString assay to quantify the expression of putative IRGs. The gene targets were selected in patients with the IFN-mediated disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and an adult patient with chronic hepatitis C who received the first dose of pegylated interferon alpha-2a. The putative target genes were validated in patients with STING-associated vasculopathy with onset in infancy (SAVI), a monogenic autoinflammatory disease caused by gain-of-function mutations in TMEM173 that encodes the viral sensor stimulator of IFN genes (STING), and had low expression in clinically active patients with the monogenic IL-1-mediated autoinflammatory disease, neonatal-onset multisystem inflammatory disease (NOMID) and in healthy controls. The score calculation on the NanoString assay is rapid and showed high reproducibility and low intra-, and interassay variability. The utility of this 28-gene IFN score may be explored in the diagnosis of patients with presumed interferonopathies and as a biomarker to assess disease activity, long-term outcome, and treatment responses.