乙型肝炎表面抗原对慢性HBV感染患者病毒特异性和整体T细胞

StephenW

Gastroenterology. 2020 Apr 14. pii: S0016-5085(20)30492-3. doi: 10.1053/j.gastro.2020.04.019. [Epub ahead of print]
Effects of Hepatitis B Surface Antigen on Virus-specific and Global T Cells in Patients With Chronic HBV infection.
Le Bert N1, Gill US2, Hong M1, Kunasegaran K1, Tan DZM1, Ahmad R1, Cheng Y3, Dutertre CA4, Heinecke A5, Rivino L6, Tan A1, Hansi NK2, Zhang M7, Xi S7, Chong Y7, Pflanz S8, Newell EW3, Kennedy PTF2, Bertoletti A9.
Author information

1
    Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore.
2
    Barts Liver Centre, Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, UK.
3
    Singapore Immunology Network, A*STAR, Singapore.
4
    Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; Singapore Immunology Network, A*STAR, Singapore.
5
    Division of Science, Yale-NUS College, Singapore.
6
    Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; School of Cellular and Molecular Medicine, University of Bristol, UK.
7
    Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
8
    Gilead Sciences, Inc., Department of Biology, Foster City, CA, USA.
9
    Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore; Singapore Immunology Network, A*STAR, Singapore. Electronic address: [email protected].

Abstract
BACKGROUND & AIMS:

Chronic hepatitis B virus (HBV) infection is characterized by the presence of defective viral envelope proteins (hepatitis B surface antigen, HBsAg) and the duration of infection-most patients acquire the infection at birth or during the first years of life. We investigated the effects of these factors on patients' lymphocyte and HBV-specific T-cell populations.
METHODS:

We collected blood samples and clinical data from 243 patients with HBV infection (3-75 years old) in the United Kingdom and China. We measured levels of HBV DNA, HBsAg, HBeAg, and alanine aminotransferase; analyzed HBV genotypes; and isolated peripheral blood mononuclear cells (PBMC). In PBMC from 48 patients with varying levels of serum HBsAg, we measured 40 markers on nature killer (NK) and T cells by mass cytometry. PBMC from 189 patients with chronic infection and 38 patients with resolved infections were incubated with HBV peptide libraries, and HBV-specific T cells were identified by interferon gamma ELISpot assays or flow cytometry. We used multivariate linear regression and performed variable selection using Akaike's information criterion to identify covariates associated with HBV-specific responses of T cells.
RESULTS:

Although T and NK cell phenotypes and functions did not change with level of serum HBsAg, numbers of HBs-specific T cells correlated with serum levels of HBsAg (r=0.3367; P<.00001). After we performed the variable selection, the multivariate linear regression model identified patient age as the only factor significantly associated with numbers of HBs-specific T cells (P=.000115). In patients younger than 30 years, HBs-specific T cells constituted 28.26% of the total HBV-specific T cells; this value decrease to 7.14% in patients older than 30 years.
CONCLUSIONS:

In an analysis of immune cells from patients with chronic HBV infection, we found the duration of HBsAg exposure, rather than quantity of HBsAg, associates with the level of anti-HBV immune response. Although the presence of HBs-specific T cells might not be required for clearance of HBV infection in all patients, strategies to restore anti-HBV immune responses should consider patients younger than 30 years.

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
KEYWORDS:

ALT; biomarker; immunosenescence; liver disease

PMID:
    32302614
DOI:
    10.1053/j.gastro.2020.04.019

StephenW

肠胃病学。 2020年4月14日。pii：S0016-5085（20）30492-3。 Doi：10.1053 / j.gastro.2020.04.019。 [Epub提前发行]
乙型肝炎表面抗原对慢性HBV感染患者病毒特异性和整体T细胞的影响。
Le Bert N1，Gill US2，Hong M1，Kunasegaran K1，Tan DZM1，Ahmad R1，Cheng Y3，Dutertre CA4，Heinecke A5，Rivino L6，Tan A1，Hansi NK2，Zhang M7，Xi S7，Chong Y7，Pflanz S8，Newell EW3，肯尼迪PTF2，贝托莱蒂A9。
作者信息

1个
新加坡杜克国大医学院新兴传染病项目。
2
英国伦敦玛丽皇后大学Barts和伦敦医学院牙科学院Barts肝脏中心，免疫生物学。
3
新加坡免疫学网络，A * STAR，新加坡。
4
新加坡杜克-国大医学院新兴传染病项目；新加坡免疫学网络，A * STAR，新加坡。
5
新加坡耶鲁国立大学科学系。
6
新加坡杜克-国大医学院新兴传染病项目；英国布里斯托大学细胞与分子医学学院。
7
中山大学附属第三医院传染病科，广州
8
美国加利福尼亚州福斯特市生物系吉利德科学公司。
9
新加坡杜克-国大医学院新兴传染病项目；新加坡免疫学网络，A * STAR，新加坡。电子地址：[email protected]。

抽象
背景与目的：

慢性乙型肝炎病毒（HBV）感染的特征在于存在有缺陷的病毒包膜蛋白（乙型肝炎表面抗原，HBsAg）和感染持续时间，大多数患者在出生时或生命的最初几年就感染了这种病毒。我们研究了这些因素对患者淋巴细胞和HBV特异性T细胞群体的影响。
方法：

我们从英国和中国的243例HBV感染（3-75岁）患者中收集了血液样本和临床数据。我们测量了HBV DNA，HBsAg，HBeAg和丙氨酸转氨酶的水平。分析HBV基因型；和分离的外周血单个核细胞（PBMC）。在来自48位血清HBsAg水平不同的患者的PBMC中，我们通过质谱检测了40种自然杀伤分子（NK）和T细胞的标志物。用HBV肽库诱导189例慢性感染患者和38例感染缓解患者的PBMC，并通过干扰素γELISpot分析或流式细胞仪鉴定HBV特异性T细胞。我们使用多元线性回归并使用Akaike信息准则执行变量选择，以识别与T细胞的HBV特异性反应相关的协变量。
结果：

尽管T和NK细胞的表型和功能并未随血清HBsAg的水平而改变，但HBs特异性T细胞的数量与血清HBsAg的水平相关（r = 0.3367； P <.00001）。在我们执行变量选择之后，多元线性回归模型将患者年龄确定为与HBs特异性T细胞数量显着相关的唯一因素（P = .000115）。在30岁以下的患者中，HBs特异性T细胞占总HBV特异性T细胞的28.26％；在30岁以上的患者中，该值降低到7.14％。
结论：

在对来自慢性HBV感染患者的免疫细胞的分析中，我们发现HBsAg暴露的持续时间而不是HBsAg的数量与抗HBV免疫反应的水平有关。尽管并非所有患者都能通过HBs特异性T细胞清除HBV感染，但恢复抗HBV免疫反应的策略应考虑30岁以下的患者。

版权所有©2020 AGA Institute。由Elsevier Inc.出版。保留所有权利。
关键字：

ALT；生物标志物免疫衰老肝病

PMID：
32302614
DOI：
10.1053 / j.gastro.2020.04.019