先天免疫在丙型肝炎病毒（HCV）感染的宿主抗病毒应答中起着重要的作用。近日证实IL-28B的单核苷酸多态性（SNP）和宿主聚乙二醇（PEG-IFN）和利巴韦林（RBV）治疗应答反应密切相关。我们的目的是确定IL-28B基因型的先天免疫相关的基因表达，并阐明其与抗病毒药物治疗应答的关系。
我们检测了88名接受PEG-IFN-2b/RBV治疗的慢性丙型肝炎患者的IL-28B的SNPs（rs8099917和rs12979860）的基因型、量化检测了病毒传感器（RIG-I，MDA5和LGP2），接头分子（IPS- 1）的相关的量化的泛素E3连接酶（RNF125），调制器（ISG15和USP18）和IL-28（IFNλ）的表达。
两个IL-28B SNP位点100％检测；54例患者拥有rs8099917 TT/rs12979860 CC（IL-28Bmajor）和34个具有rs8099917 TG/rs12979860 CT（IL-28Bminor）与IL-28B major 相比较，IL-28Bminor的病毒传感器和调制器肝表达明显上调，（≈3.3倍，P<0.001）。然而，IL-28B minor IPS- 1的表达显著降低（1.2倍，P= 0.028）。IL-28B基因型分层分析无病毒学应答者（NVR）的病毒感应器和调制器的表达显著增高（≈2.6倍，P<0.001）。多变量和ROC分析提示， RIG-I和ISG15高表达和RIG-I/IPS-1表达率分别为NVR的独立危险因素。Western印迹证实IL-28Bminor中IPS- 1下调，IPS- 1蛋白裂解程度与变化的治疗反应相关。
先天免疫相关的基因表达与IL-28B基因型和PEG- IFN/RBV应答密切相关。IL-28B少数等位基因型和较高的RIG-I 和ISG15的表达和RIG-I/IPS-1比例是NVR的独立（预测）因子。
吉林大学第一医院肝胆胰内科 牛俊奇 摘译
本文首次发表于[Hepatology, 2012, 55(1):20-29. doi: 10.1002/hep.24623]
Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response
Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection.Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon (PEG-IFN ) and ribavirin (RBV) were shown to be strongly associated.We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment.
We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFN -2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125),modulators (ISG15 and USP18), and IL28 (IFNλ).
Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈3.3-fold, P < 0.001).
However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈2.6-fold, P < 0.001).Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response.
Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFN /RBV.Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.
