Jiang Penglei, Jia Hongyu, Qian Xinyue, Tang Tian, Han Yingli, Zhang Zhaoru, Jiang Lingli, Yu Zebin, Zheng Lin, Yu Guodong, Cai Huan, Zhang Shanyan, Zhang Xiaoli, Gu Jueqing, Ye Chanyuan, Yang Lisha, Lu Yingfeng, Liu Heng, Lu Xiaoqing, Jin Ciliang, Ren Yue, Lu Miaomiao, Xu Lingling, Yu Jiong, Jin Xi, Yang Yida, Qian Pengxu
Bone Marrow Transplantation Center of the First Affiliated Hospital and Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
Hepatology. 2024 Jan 1;79(1):167-182. doi: 10.1097/HEP.0000000000000524. Epub 2023 Jun 27.
Chronic hepatitis B (CHB) is caused by HBV infection and affects the lives of millions of people worldwide by causing liver inflammation, cirrhosis, and liver cancer. Interferon-alpha (IFN-α) therapy is a conventional immunotherapy that has been widely used in CHB treatment and achieved promising therapeutic outcomes by activating viral sensors and interferon-stimulated genes (ISGs) suppressed by HBV. However, the longitudinal landscape of immune cells of CHB patients and the effect of IFN-α on the immune system are not fully understood.
Here, we applied single-cell RNA sequencing (scRNA-seq) to delineate the transcriptomic landscape of peripheral immune cells in CHB patients before and after PegIFN-α therapy. Notably, we identified three CHB-specific cell subsets, pro-inflammatory (Pro-infla) CD14+ monocytes, Pro-infla CD16+ monocytes and IFNG+ CX3CR1- NK cells, which highly expressed proinflammatory genes and positively correlated with HBsAg. Furthermore, PegIFN-α treatment attenuated percentages of hyperactivated monocytes, increased ratios of long-lived naive/memory T cells and enhanced effector T cell cytotoxicity. Finally, PegIFN-α treatment switched the transcriptional profiles of entire immune cells from TNF-driven to IFN-α-driven pattern and enhanced innate antiviral response, including virus sensing and antigen presentation.
Collectively, our study expands the understanding of the pathological characteristics of CHB and the immunoregulatory roles of PegIFN-α, which provides a new powerful reference for the clinical diagnosis and treatment of CHB.
慢性乙型肝炎（CHB）由乙肝病毒（HBV）感染引起，通过引发肝脏炎症、肝硬化和肝癌影响着全球数百万人的生活。α干扰素（IFN-α）疗法是一种传统的免疫疗法，已广泛应用于CHB治疗，并通过激活被HBV抑制的病毒传感器和干扰素刺激基因（ISGs）取得了良好的治疗效果。然而，CHB患者免疫细胞的纵向特征以及IFN-α对免疫系统的影响尚未完全明确。
在此，我们应用单细胞RNA测序（scRNA-seq）来描绘聚乙二醇化干扰素-α（PegIFN-α）治疗前后CHB患者外周免疫细胞的转录组特征。值得注意的是，我们鉴定出三个CHB特异性细胞亚群，即促炎（Pro-infla）CD14+单核细胞、Pro-infla CD16+单核细胞和IFNG+ CX3CR1-自然杀伤细胞（NK细胞），它们高度表达促炎基因且与乙肝表面抗原（HBsAg）呈正相关。此外，PegIFN-α治疗降低了过度活化单核细胞的百分比，增加了长寿初始/记忆T细胞的比例，并增强了效应T细胞的细胞毒性。最后，PegIFN-α治疗将整个免疫细胞的转录谱从肿瘤坏死因子（TNF）驱动模式转变为IFN-α驱动模式，并增强了先天性抗病毒反应，包括病毒感知和抗原呈递。
总体而言，我们的研究扩展了对CHB病理特征和PegIFN-α免疫调节作用的理解，为CHB的临床诊断和治疗提供了新的有力参考。
