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中华消化病与影像杂志(电子版) ›› 2024, Vol. 14 ›› Issue (04) : 343 -347. doi: 10.3877/cma.j.issn.2095-2015.2024.04.011

论著

HBV感染患者外周血ISGs表达水平变化及其与干扰素治疗疗效的关系
胡静1,†(), 杨秀锦2, 侯志云1   
  1. 1. 102600　北京，首都医科大学大兴教学医院感染内科
    2. 100040　北京，首都医科大学石景山教学医院急诊科
  • 收稿日期:2024-02-18 出版日期:2024-08-01
  • 通信作者: 胡静

Changes of peripheral blood ISGs and their relationship with curative effect of interferon therapy in patients with HBV infection

Jing Hu1,†(), Xiujin Yang2, Zhiyun Hou1   

  1. 1. Department of Infectious Disease, Daxing Teaching Hospital of Capital Medical University, Beijing 102600, China
    2. Department of Emergency, Shijingshan Teaching Hospital of Capital Medical University, Beijing 100040, China
  • Received:2024-02-18 Published:2024-08-01
  • Corresponding author: Jing Hu
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胡静, 杨秀锦, 侯志云. HBV感染患者外周血ISGs表达水平变化及其与干扰素治疗疗效的关系[J]. 中华消化病与影像杂志(电子版), 2024, 14(04): 343-347.

Jing Hu, Xiujin Yang, Zhiyun Hou. Changes of peripheral blood ISGs and their relationship with curative effect of interferon therapy in patients with HBV infection[J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2024, 14(04): 343-347.

目的

探讨HBV感染患者外周血干扰素刺激基因（ISGs）表达水平变化及其与干扰素治疗疗效的关系。

方法

选取首都医科大学大兴教学医院2018年4月至2023年5月收治的80例HBV感染患者纳入HBV组，另选取同期进行健康体检者80例作为对照组。对比两组外周血黏病毒抗性蛋白A（MxA）mRNA、泛素特异性蛋白酶18（USP18）mRNA、细胞因子信号转导抑制因子3（SOCS3）mRNA表达水平，HBV组患者均给予重组人干扰素α-2b持续治疗24周，依照干扰素应答情况，分为干扰素应答组（n=38）与干扰素无应答组（n=42）两个亚组，通过Logistic回归分析外周血指标与干扰素应答的关系，并观察HBV组患者干扰素治疗前后MxA mRNA、USP18 mRNA、SOCS3 mRNA水平变化。

结果

HBV组治疗前外周血MxA mRNA水平低于对照组，USP18 mRNA、SOCS3 mRNA水平高于对照组（P<0.05）；干扰素应答组治疗前外周血MxA mRNA水平高于干扰素无应答组，USP18 mRNA、SOCS3 mRNA水平低于干扰素无应答组（P<0.05）；Logistic回归分析显示USP18 mRNA、SOCS3 mRNA高表达是HBV感染患者干扰素无应答危险因素，MxA mRNA高表达是干扰素应答保护因素；干扰素应答组治疗前、治疗2周、12周、24周后外周血MxA mRNA表达水平高于干扰素无应答组，USP18 mRNA、SOCS3 mRNA表达水平低于干扰素无应答组（P<0.05）。

结论

HBV感染者应用干扰素治疗中，MxA高表达、USP18、SOCS3低表达者具有较佳的干扰素应答疗效。

关键词: 乙型肝炎病毒, 干扰素, 干扰素刺激基因, 治疗应答
Objective

To explore the changes of peripheral blood interferon-stimulated genes (ISGs) and their relationship with curative effect of interferon therapy in patients with hepatitis B virus (HBV) infection.

Methods

A total of 80 patients with HBV infection and 80 healthy controls in Daxing Teaching Hospital of Capital Medical University were enrolled as HBV group and control group between April 2018 and May 2023, respectively. The mRNA levels of myxovirus resistance protein A (MxA), ubiquitin-specific protease 18 (USP18) and suppressors of cytokine signaling 3 (SOCS3) in peripheral blood were compared between the two groups. The patients in the HBV group were treated with recombinant human interferon α-2b for 24 weeks. According to interferon response, they were divided into response group (n=38) and non-response group (n=42). The relationship between peripheral blood indexes and interferon response was analyzed by Logistic regression analysis, and changes of MxA mRNA, USP18 mRNA and SOCS3 mRNA before and after interferon treatment in the HBV group were observed.

Results

Before treatment, level of peripheral blood MxA mRNA in the HBV group was lower than that in the control group, while levels of USP18 mRNA and SOCS3 mRNA were higher than those in the control group (P<0.05). Before treatment, level of peripheral blood MxA mRNA in the response group was higher than that in the non-response group, while levels of USP18 mRNA and SOCS3 mRNA were lower than those in the non-response group (P<0.05). Logistic regression analysis showed that high expressions of USP18 mRNA and SOCS3 mRNA were risk factors of interferon non-response, while high expression of MxA mRNA was a protective factor of interferon response. Before treatment, after 2 weeks, 12 weeks and 24 weeks of treatment, level of peripheral blood MxA mRNA in the interferon response group was higher than that in the non-response group, while levels of USP18 mRNA and SOCS3 mRNA were lower than those in the non-response group (P<0.05).

Conclusion

In the treatment of HBV infection with interferon, interferon response effect is better in those with high expression of MxA and low expressions of USP18 and SOCS3.

Key words: Hepatitis B virus, Interferon, Interferon-stimulated genes, Treatment response
表1 引物序列
因子 上游引物 下游引物
MxA mRNA ACAATCAGCCTGGTGGTGGTC CCTCCCCTACAGTTTCCTCTCC
USP18 mRNA CTGTGCCATGGAGAGTAGCA AGGTGGATTGTCAGGGTCTG
SOCS3 mRNA TGCGCCTCAAGACCTTCAGC GATGCGCAGGTTCTTGGTCC
GAPDH mRNA ACATCATCCCTGCCTCTAC TCAAAGGTGGAGGAGTGG
表2 HBV组与对照组外周血ISGs基因表达水平（±s）
组别 例数 MxA mRNA USP18 mRNA SOCS3 mRNA
HBV组 80 0.522±0.091 0.059±0.014 1.014±0.213
对照组 80 0.917±0.176 0.016±0.004 0.218±0.037
t   17.831 26.415 32.922
P   <0.001 <0.001 <0.001
表3 不同临床特征HBV患者干扰素应答情况比较
组别 例数 性别(例) 年龄(岁,±s) 治疗前丙氨酸转氨酶(Log10 U/L,±s) 治疗前HBV DNA(Log10copies/mL,±s) 肝硬化(例)
男 女 否 是
干扰素应答组 38 21 17 53.87±10.96 2.33±0.14 7.21±0.71 26 12
干扰素无应答组 42 23 19 54.76±11.28 2.31±0.13 7.50±0.92 25 17
t/χ2   0.002 0.357 0.663 1.566 0.683
P   0.964 0.722 0.51 0.121 0.408
表4 干扰素应答组与干扰素无应答组治疗前ISGs基因表达水平比较（±s）
组别 例数 MxA mRNA USP18 mRNA SOCS3 mRNA
干扰素应答组 38 0.651±0.101 0.043±0.011 0.774±0.194
干扰素无应答组 42 0.406±0.061 0.074±0.021 1.231±0.269
t   13.275 8.142 8.634
P   <0.001 <0.001 <0.001
表5 HBV染患者干扰素应答影响因素分析
因素 β SE Wald P Exp(β) 95% CI
MxA mRNA -0.856 0.294 8.477 0.004 0.425 0.239~0.756
USP18 mRNA 2.873 0.835 11.839 0.001 17.690 4.443~26.880
SOCS3 mRNA 0.467 0.149 9.823 0.002 1.595 1.191~2.136
表6 干扰素应答组与干扰素无应答组患者治疗前后ISGs基因表达水平变化（±s）
组别 例数   MxA mRNA USP18 mRNA SOCS3 mRNA
干扰素应答组 38 治疗前 0.651±0.101 0.043±0.011 0.774±0.194
  治疗2周后 0.426±0.083 0.072±0.019 0.996±0.221
  治疗12周后 0.418±0.079 0.069±0.020 0.992±0.189
  治疗24周后 0.433±0.064 0.070±0.023 0.998±0.193
干扰素无应答组 42 治疗前 0.406±0.061 0.074±0.021 1.231±0.269
  治疗2周后 0.312±0.074 0.097±0.025 1.506±0.348
  治疗12周后 0.303±0.069 0.093±0.029 1.493±0.317
  治疗24周后 0.329±0.057 0.095±0.030 1.515±0.286
F组间/F时间/F交互     302.200/91.730/16.330 102.600/22.040/7.381 287.800/17.930/11.426
P     <0.001 <0.001 <0.001
[1]
Li H, Barbara C, Dominic D, et al. Incident hepatitis B virus infection and immunisation uptake in Australian prison inmates - ScienceDirect[J]. Vaccine, 2020, 38(16): 3255-3260.
[2]
Li CL, Li CY, Lin YY, et al. Androgen Receptor Enhances Hepatic Telomerase Reverse Transcriptase Gene Transcription After Hepatitis B Virus Integration or Point Mutation in Promoter Region[J]. Hepatology, 2019, 69(2): 498-512.
[3]
Bockmann JH, Stadler D, Xia Y, et al. Comparative Analysis of the Antiviral Effects Mediated by Type I and III Interferons in Hepatitis B Virus-Infected Hepatocytes[J]. J Infect Dis, 2019, 220(4): 567-577.
[4]
Xia YC, Martin S, Volker M, et al. PASylated interferon α efficiently suppresses hepatitis B virus and induces anti-HBs seroconversion in HBV-transgenic mice[J]. Antiviral Res, 2019, 161(1): 134-143.
[5]
Chen X, Yue RC, Li XM, et al. Surfactant protein A modulates the activities of the JAK/STAT pathway in suppressing Th1 and Th17 polarization in murine OVA-induced allergic asthma[J]. Lab Invest, 2021, 22(9): 1-10.
[6]
Hubel P, Urban C, Bergant V, et al. A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape[J]. Nat Immunol, 2019, 20(4): 493-502.
[7]
中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南[J]. 中华内科杂志, 2005, 45(1): 3-15.
[8]
凡豪志, 张云, 岳明, 等. CC趋化因子细胞受体5基因多态性与慢性丙肝干扰素疗效关联性的研究[J]. 中华疾病控制杂志, 2018, 22(10): 1020-1023.
[9]
赖思敏, 赖小丽, 黄汐, 等. 核苷(酸)类似物经治序贯聚乙二醇干扰素治疗慢性乙型肝炎的荟萃分析[J]. 中国感染与化疗杂志, 2019, 24(5): 489-494.
[10]
Yuan W, Huang D, Wu D, et al. Pegylated Interferon-ɑ(IFN-ɑ) Enhances the Inhibitory Effect of Natural Killer Cells on Regulatory T Cells via IFN-γ in Chronic Hepatitis B[J]. J Infect Dis, 2021, 19(4): 216-219.
[11]
Kerr CH, Skinnider MA, Andrews D, et al. Dynamic rewiring of the human interactome by interferon signaling[J]. Genome Biol, 2020, 21(1): 2050-2053.
[12]
陈邦涛, 冯旭娇, 杨青青, 等. 神经前体细胞表达发育调控样基因4在乙型肝炎病毒复制中的作用[J]. 中华传染病杂志, 2020, 38(8): 501-506.
[13]
Millrain M, Chandler P, Dazzi F, et al. Examination of HY response: T cell expansion, immunodominance, and cross-priming revealed by HY tetramer analysis[J]. J Immunol, 201, 167(7): 3756-3764.
[14]
张小梅, 雷青松, 秦波, 等. 泛素特异性蛋白酶18抑制IFNα抗HBV活性但并不抑制IFNλ抗HBV的活性[J]. 中国生物化学与分子生物学报, 2018, 34(9): 954-961.
[15]
Gruber C, Martin-Fernandez M, Ailal F, et al. Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy[J]. J Exp Med, 2020, 217(5): 319-322.
[16]
Xiang J, Zhang X, Fu J, et al. USP18 Overexpression Protects against Focal Cerebral Ischemia Injury in Mice by Suppressing Microglial Activation[J]. Neuroscience, 2019, 419(11): 121-128.
[17]
Lee K, Jeon J, Kim SJ, et al. 241-LB: Positive Regulation of JAK/STAT at Signaling with SOCS3-Derived Cell-Permeable Binding Domain to ObR Induces Anti-obesity Effect[J]. Diabetes, 2020, 69(1): 241-243.
[18]
王永力, 吴文煜, 尤洁, 等. 核苷(酸)类似物经治慢性乙型肝炎患者干扰素α治疗过程中细胞因子信号抑制因子3的表达与抗病毒疗效的关系[J]. 中华肝脏病杂志, 2019, 27(1): 27-32.
[19]
钟瑞雪, 谢伟贤, 黄泽棋, 等. 干扰素刺激基因表达对Peg-IFN抗乙型肝炎病毒免疫应答的影响[J]. 基因组学与应用生物学, 2019, 38(1): 478-483.
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