Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response
Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response
复制标题
DOI：
10.1053/j.gastro.2008.02.019
复制
发表时间：
2008-05-01
期刊：
影响因子：
29.4
通讯作者：
Miyake, Shozo
中科院分区：
文献类型：
--
作者：
Asahina, Yasuhiro;Izumi, Namiki;Miyake, Shozo
背景和目的：涉及先天免疫的分子在治疗反应中的临床意义仍不清楚。目的是阐明慢性丙型肝炎（CH-C）抗病毒治疗耐药的潜在机制以及基因定量的预测有用性。方法：我们对 74 名接受聚乙二醇化干扰素 a-2b 和利巴韦林治疗的 CH-C 患者以及 5 名非病毒对照患者进行了人体研究。对病毒传感器、接头分子、相关泛素 E3 连接酶和调节剂的表达进行了定量。结果：与具有相对构成性 Cardif 的非丙型肝炎病毒患者相比，CH-C 患者的肝脏 RIG-I、MDA5、LGP2、ISG15 和 USP18 上调 2 至 8 倍。与短暂（TR）或持续病毒学应答者（SVR）相比，非病毒学应答者（NVR）的肝脏RIG-I、MDAS和LGP2显着上调。 Cardif 和 RNF125 与 RIG-I 呈负相关，并且在 NVR 中显着受到抑制。 RIG-I/Cardif 和 RIG-I/RNF125 比率的临床反应差异非常明显（NVR/TR/SVR 分别 = 1.3:0.6:0.4 和 2.3:1.3:0.8）。与病毒传感器一样，ISG15 和 USP18 在 NVR 中显着上调（分别是 4 倍和 2.3 倍）。多变量和接收者操作员特征分析显示较高的 RIG-I/Cardif 比率、ISG15 和 USP18 预测的 NVP。 NVR中的Lower Cardif通过Western blot中的蛋白水平得到证实。此外，外周血单核细胞对治疗的转录反应快速而强烈，但 Cardif 除外，不仅呈阳性（RIG-I、ISG15 和 USP18），而且呈负调节方式（RNF125）。结论：NVR 可能在其先天免疫反应中采取了不同的平衡。高 RIG-I/Cardif 和 RIG-I/RNF125 比率以及 ISG15 和 USP18 对于识别 NVR 很有用。
Background & Aims: Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C). Methods: We conducted a human study in 74 CH-C patients treated with pegylated interferon a-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified. Results: Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with non-hepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDAS, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVP. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125). Conclusions: NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR.