γ-干扰素+白介素-17+Th17 细胞在慢性乙型肝炎病毒感染相关肝损伤中的临床意义和特性。

Clinical Significance and Properties of IFN-γ+IL-17+ Th17 Cells in Liver Injury Associated with Chronic Hepatitis B Virus Infection.

机构信息

Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

出版信息

Digestion. 2022;103(6):438-450. doi: 10.1159/000526924. Epub 2022 Oct 20.

DOI:10.1159/000526924

PMID:36265446

Abstract

INTRODUCTION

Our previous study demonstrated that intrahepatic Th17 cells exacerbated the progression of chronic hepatitis B virus (HBV) infection. Meanwhile, we found a small group of IFN-γ and IL-17 double-positive Th17 cells (IFN-γ+IL-17+ Th17 cells) in liver tissues. This study aimed to investigate the clinical significance and properties of IFN-γ+IL-17+ Th17 cells in liver injury associated with chronic HBV infection.

METHODS

The frequencies of CD4+ Th cells, Tregs, and CD4+ T cells expressing specific chemokine receptors in the blood and liver tissues were detected using flow cytometry. The chemotaxis of C C chemokine receptor 5 (CCR5) and C-X-C chemokine receptor 3 (CXCR3) toward IFN-γ+IL-17+ Th17 cells and Tregs was evaluated by transwell chemotactic assay. Analyses of different variables were performed using GraphPad Prism v 5.01 and IBM SPSS Statistics 23.0. HBV-specific IFN-γ+IL-17+ Th17 cells were investigated using a cell stimulation assay with HBV antigens in vitro.

RESULTS

The frequencies of IFN-γ+IL-17+ Th17, Th17 cells, and Tregs in the blood were increased from normal controls to chronic hepatitis B (CHB) and acute-on-chronic liver failure (ACLF). The same trend could also be observed in CHB liver tissues compared to those in CHB blood specimens. Furthermore, the frequencies of IFN-γ+IL-17+ Th17 cells were positively associated with Th17 cells, Th17 cell-related cytokines (IL-17 and IL-6), HBV DNA load, and the levels of HBsAg, HBeAg, and ALT. The ratios of IFN-γ+IL-17+ Th17 cells to Tregs extremely decreased in ACLF blood specimens compared with those in CHB blood specimens. Additionally, CCR5 and CXCR3 were conducive to the recruitment of IFN-γ+IL-17+ Th17 cells and Tregs to liver tissue.

CONCLUSIONS

IFN-γ+IL-17+ Th17 cells have Th17 cell-like properties in the progression of chronic HBV infection. CCR5 and CXCR3 facilitated the recruitment of IFN-γ+IL-17+ Th17 cells and Tregs to the liver. Importantly, the ratio of IFN-γ+IL-17+ Th17 cells to Tregs might be an effective assessment indicator of the severity of liver injury.

摘要

简介

我们之前的研究表明，肝内 Th17 细胞加剧了慢性乙型肝炎病毒（HBV）感染的进展。同时，我们在肝组织中发现了一小群 IFN-γ 和 IL-17 双阳性 Th17 细胞（IFN-γ+IL-17+ Th17 细胞）。本研究旨在探讨与慢性 HBV 感染相关肝损伤中 IFN-γ+IL-17+ Th17 细胞的临床意义和特性。

方法

采用流式细胞术检测血液和肝组织中 CD4+ Th 细胞、Tregs 和表达特定趋化因子受体的 CD4+ T 细胞的频率。通过 Transwell 趋化实验评估 C C 趋化因子受体 5（CCR5）和 C-X-C 趋化因子受体 3（CXCR3）对 IFN-γ+IL-17+ Th17 细胞和 Tregs 的趋化作用。采用 GraphPad Prism v 5.01 和 IBM SPSS Statistics 23.0 分析不同变量。体外使用 HBV 抗原进行细胞刺激试验研究 HBV 特异性 IFN-γ+IL-17+ Th17 细胞。

结果

从正常对照到慢性乙型肝炎（CHB）和慢加急性肝衰竭（ACLF），血液中 IFN-γ+IL-17+ Th17、Th17 细胞和 Tregs 的频率增加。与 CHB 血液标本相比，CHB 肝组织也呈现出相同的趋势。此外，IFN-γ+IL-17+ Th17 细胞的频率与 Th17 细胞、Th17 细胞相关细胞因子（IL-17 和 IL-6）、HBV DNA 载量以及 HBsAg、HBeAg 和 ALT 水平呈正相关。与 CHB 血液标本相比，ACLF 血液标本中 IFN-γ+IL-17+ Th17 细胞与 Tregs 的比值极显著降低。此外，CCR5 和 CXCR3 有利于 IFN-γ+IL-17+ Th17 细胞和 Tregs 向肝组织募集。

结论

IFN-γ+IL-17+ Th17 细胞在慢性 HBV 感染的进展中具有 Th17 细胞样特性。CCR5 和 CXCR3 促进了 IFN-γ+IL-17+ Th17 细胞和 Tregs 向肝脏的募集。重要的是，IFN-γ+IL-17+ Th17 细胞与 Tregs 的比值可能是评估肝损伤严重程度的有效评估指标。