Pathogenesis of chronic hepatitis C and hepatocellular carcinoma and predictive factors determined by data mining

背景技术背景：干扰素（IFN）和利巴韦林（RBV）耐药机制尚未完全阐明，在开始治疗前预测治疗反应是困难的。RIG-I和相关的MDA 5通过检测细胞内病毒dsRNA启动宿主抗病毒应答。Cardif（ISP-I，MAVS，VISA）是连接RIG-I传感与下游信号传导的衔接子分子。另一方面，LGP 2（属于RIG-I家族的解旋酶）和E3泛素连接酶已显示负调节RIG-I传感。此外，这些分子被ISG 15（一种泛素样蛋白）ISG化。然而，这些先天免疫系统在治疗应答方面的临床意义尚不清楚。目的：阐明PEG-IFN + RBV耐药的潜在机制，并确定先天免疫系统的分析是否有助于预测治疗应答。我们研究了74例慢性丙型肝炎病毒（HCV）基因型lb治疗的患者， ...更多信息 用PEG-IFN α-2b联合RBV治疗48周，5例非病毒性肝病患者。治疗前肝脏RIG-I、Cardif MDA 5、LGP 2、ISG 15、USP 18（从ISGylated蛋白中特异性去除ISMS）的mRNA表达，以及治疗期间血清HCV动力学通过实时PCR测定。结果：34例患者为持续病毒学应答者（SVR），24例为短暂应答者（TR），20例为非病毒学应答者（NVR）。除Cardif外，所有转录本的肝脏水平均为2。HCV感染者比非HCV感染者高8倍。与TR或SVR相比，NVR中RIG-I、MDA 5和LGP 2的表达显著上调。Cardif表达与RIG-I表达呈负相关，在NVR中被显著抑制。NVR和SVR或TR之间RIG-I/Cardif表达比率的差异是显著的（NVR/PR/SVR = 1.2/0.6/0.5拷贝/对照）。与RIG-I和MDA 5一样，ISG 15和USP 18表达在NVR中显著上调（ISG 15，NVR/TR/SVR = 0.8/0.4/0.2拷贝/对照; USP 18，NVRTR/SVR = 0.9/0.6/0.4拷贝/对照）。RIG-I/Cardif比值和MDA 5、ISG 15和USP 18的表达与HCV动力学第一和第二阶段的病毒下降率显著相关。多变量和ROC分析显示，较高的RIG-I/Cardif比率和较高的MDA 5，ISG 15和USP 18的表达预测NW。结论：细胞内传感器及其调节器在HCV感染后，特别是在NVR中，被不同程度地上调。定量涉及先天免疫系统的肝脏基因表达可用于识别NVR风险较高的患者。少

BACKGROUND: Mechanisms involving resistance to interferon (IFN) and ribavirin (RBV) have wit been fully elucidated, and prediction of treatment responses before initiation of therapy is difficult. RIG-I and the related MDA5 initiate the host antiviral response by detecting intracellular viral dsRNA. Cardif (ISP-I, MAVS, VISA) is an adaptor molecule that connects RIG-I sensing to downstream signaling. On the other hand, LGP2, a helicase belonging RIG-I family, and an E3 ubiquitin ligase have been shown to negatively regulate RIG-I sensing. Moreover, these molecules are ISGylated by ISG15, a ubiquitin-like protein However; the clinical significance of these innate immune systems in terms of treatment response is unclear.AIM: To elucidate the mechanisms underlying resistance to PEG-IFN plus RBV, and to determine whether analysis of the innate immune system is useful in predicting treatment responses.METHODS: We studied 74 chronic hepatitis C virus (HCV) patients with genotype lb treated w … More ith PEG-IFN alfa-2b plus RBV for 48 weeks and 5 patients with non-viral liver disease. Pretreatment hepatic mRNA expressions of RIG-I, Cardif MDA5, LGP2, ISG15, USP18 (a specific remover of ISMS from ISGylated protein), and serum HCV dynamics during therapy were measured by real-time PCR. G3PDH and HMB were used as internal controls.RESULTS: Thirty-four patients were sustained virological responders (SVR), 24 were transient responders (TR), and 20 were non-virological responders (NVR). The hepatic levels of all transcripts except Cardif were 2. to 8-fold higher in HCV patients than non-HCV patients. RIG-I, MDA5, and LGP2 expression was significantly up-regulated in NVR compared with TR or SVR. Cardif expression negatively correlated with RIG-I expression and was significantly suppressed in NVR. The difference between NVR and SVR or TR in the RIG-I/Cardif expression ratio was pronounced (NVR/PR/SVR = 1.2/0.6/0.5 copies/control). Like RIG-I and MDA5, ISG15 and USP18 expression was significantly up-regulated in NVR (ISG15, NVR/TR/SVR = 0.8/0.4/0.2 copies/control; USP18, NVRTR/SVR = 0.9/0.6/0.4 copies/control). The RIG-I/Cardif ratio and the expression of MDA5, ISG15, and USP18 significantly correlated with viral decline rates in the first and second phases of HCV dynamics. Multivariate and ROC analyses revealed that a higher ratio of RIG-I/Cardif and a higher expression of MDA5, ISG15, and USP18 predicted NW.CONCLUSION: Intracellular sensors and their regulators were variously up-regulated upon HCV infection especially in NVR Quantifying hepatic gene expression involving an innate immune system is of use in identifying patients who are at a higher risk for NVR. Less