Multi-parametric analysis of human livers reveals variation in intrahepatic inflammation across phases of chronic hepatitis B infection

免疫系统 CXCL10型 免疫学 趋化因子 乙型肝炎病毒 炎症 生物 CXCL9型 HBeAg CXCR3型 病毒 乙型肝炎表面抗原 趋化因子受体
作者
Noe Rico Montanari,Ricardo Ramírez,Abhishek Aggarwal,Nicholas van Buuren,Michael Doukas,Christina Moon,Scott Turner,Lauri Diehl,Li Li,José D. Debes,Becket Feierbach,André Boonstra
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:77 (2): 332-343 被引量:39
标识
DOI:10.1016/j.jhep.2022.02.016
摘要

•RNA-Seq and multiplex immunofluorescence (mIF) was performed on liver biopsies to characterize the HBV clinical phases.•Chronic HBV livers were characterized by higher immune-gene expression and leukocyte infiltrate than healthy livers.•ALT determined immune gene expression profiles in livers of IA and ENEG patients.•Immune-exhaustion profiles were observed in livers of IA and ENEG patients.•Leukocyte infiltrate correlated with serum ALT, but not with HBV DNA or intrahepatic HBcAg and HBsAg. Background & AimsChronic HBV is clinically categorized into 4 phases by a combination of serum HBV DNA levels, HBeAg status and alanine aminotransferase (ALT): immunotolerant (IT), immune-active (IA), inactive carrier (IC) and HBeAg-negative hepatitis (ENEG). Immune and virological measurements in the blood have proven useful but are insufficient to explain the interrelation between the immune system and the virus since immune dynamics differ in the blood and liver. Furthermore, the inflammatory response in the liver and parenchymal cells cannot be fully captured in blood.MethodsImmunological composition and transcriptional profiles of core needle liver-biopsies in chronic HBV phases were compared to those of healthy controls by multiplex immunofluorescence and RNA-sequencing (n = 37 and 78, respectively) analyses.ResultsIrrespective of the phase-specific serological profiles, increased immune-gene expression and frequency was observed in chronic HBV compared to healthy livers. Greater transcriptomic deregulation was seen in IA and ENEG (172 vs. 243 DEGs) than in IT and IC (13 vs. 35 DEGs) livers. Interferon-stimulated genes, immune-activation and exhaustion genes (ICOS, CTLA4, PDCD1) together with chemokine genes (CXCL10, CXCL9) were significantly induced in IA and ENEG livers. Moreover, distinct immune profiles associated with ALT elevation and a more accentuated immune-exhaustion profile (CTLA4, TOX, SLAMF6, FOXP3) were observed in ENEG, which set it apart from the IA phase (LGALS9, PDCD1). Interestingly, all HBV phases showed downregulation of metabolic pathways vs. healthy livers (fatty and bile acid metabolism). Finally, increased leukocyte infiltrate correlated with serum ALT, but not with HBV DNA or viral proteins.ConclusionOur comprehensive multi-parametric analysis of human livers revealed distinct inflammatory profiles and pronounced differences in intrahepatic gene profiles across all chronic HBV phases in comparison to healthy liver.Lay summaryImmunological studies on chronic HBV remain largely restricted to assessment of peripheral responses due to the limited access to the site of infection, the liver. In this study, we comprehensively analyzed livers from a well-defined cohort of patients with chronic HBV and uninfected controls with state-of-the-art techniques, and evaluated the differences in gene expression profiles and inflammation characteristics across distinct disease phases in patients with chronic HBV. Chronic HBV is clinically categorized into 4 phases by a combination of serum HBV DNA levels, HBeAg status and alanine aminotransferase (ALT): immunotolerant (IT), immune-active (IA), inactive carrier (IC) and HBeAg-negative hepatitis (ENEG). Immune and virological measurements in the blood have proven useful but are insufficient to explain the interrelation between the immune system and the virus since immune dynamics differ in the blood and liver. Furthermore, the inflammatory response in the liver and parenchymal cells cannot be fully captured in blood. Immunological composition and transcriptional profiles of core needle liver-biopsies in chronic HBV phases were compared to those of healthy controls by multiplex immunofluorescence and RNA-sequencing (n = 37 and 78, respectively) analyses. Irrespective of the phase-specific serological profiles, increased immune-gene expression and frequency was observed in chronic HBV compared to healthy livers. Greater transcriptomic deregulation was seen in IA and ENEG (172 vs. 243 DEGs) than in IT and IC (13 vs. 35 DEGs) livers. Interferon-stimulated genes, immune-activation and exhaustion genes (ICOS, CTLA4, PDCD1) together with chemokine genes (CXCL10, CXCL9) were significantly induced in IA and ENEG livers. Moreover, distinct immune profiles associated with ALT elevation and a more accentuated immune-exhaustion profile (CTLA4, TOX, SLAMF6, FOXP3) were observed in ENEG, which set it apart from the IA phase (LGALS9, PDCD1). Interestingly, all HBV phases showed downregulation of metabolic pathways vs. healthy livers (fatty and bile acid metabolism). Finally, increased leukocyte infiltrate correlated with serum ALT, but not with HBV DNA or viral proteins. Our comprehensive multi-parametric analysis of human livers revealed distinct inflammatory profiles and pronounced differences in intrahepatic gene profiles across all chronic HBV phases in comparison to healthy liver.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
圆锥香蕉应助科研通管家采纳,获得20
刚刚
怕黑半仙应助科研通管家采纳,获得10
刚刚
刚刚
圆锥香蕉应助科研通管家采纳,获得20
刚刚
科研通AI5应助科研通管家采纳,获得10
刚刚
刚刚
领导范儿应助科研通管家采纳,获得10
刚刚
1秒前
1秒前
Cml完成签到,获得积分10
2秒前
Liufgui应助牛文文采纳,获得10
3秒前
chun发布了新的文献求助10
4秒前
YI应助南兮采纳,获得10
4秒前
orixero应助颜云尔采纳,获得10
5秒前
anna发布了新的文献求助10
5秒前
YWang发布了新的文献求助10
8秒前
8秒前
NiNi完成签到,获得积分10
10秒前
悦耳寒松发布了新的文献求助10
10秒前
sijing发布了新的文献求助10
11秒前
7777完成签到,获得积分10
11秒前
求求了,让孩子毕业吧完成签到,获得积分10
12秒前
12秒前
15秒前
我是老大应助LiuJinhui采纳,获得10
16秒前
19秒前
量子星尘发布了新的文献求助10
19秒前
清久完成签到,获得积分10
20秒前
牛马码字员完成签到,获得积分10
20秒前
橙果果发布了新的文献求助20
21秒前
所所应助11采纳,获得10
21秒前
tt大耳朵完成签到,获得积分10
22秒前
22秒前
23秒前
枫之林发布了新的文献求助10
23秒前
辛俊辰发布了新的文献求助10
23秒前
xiao完成签到 ,获得积分10
23秒前
lemongulf完成签到 ,获得积分10
24秒前
发表多篇高ifsci的第一作者完成签到,获得积分20
25秒前
阅遍SCI完成签到,获得积分10
25秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989069
求助须知:如何正确求助?哪些是违规求助? 3531351
关于积分的说明 11253589
捐赠科研通 3269939
什么是DOI,文献DOI怎么找? 1804851
邀请新用户注册赠送积分活动 882074
科研通“疑难数据库(出版商)”最低求助积分说明 809073