HBsAg和HBcrAg水平對慢性乙型肝炎病毒感染患者HBV特異性T細胞

StephenW

HBsAg和HBcrAg水平對慢性乙型肝炎病毒感染患者HBV特異性T細胞表型和功能的影響
Elmira Aliabadi 1 2 3 , Melanie Urbanek-Quaing 1 2 3 , Benjamin Maasoumy 1 3 , Birgit Bremer 1 , Martin Grasshoff 4 , Yang Li 2 4 5 , Christian E Niehaus 1 2 , Heiner Wedemeyer 1 RM 3 , Anke 12 , 馬庫斯康伯格 6 2 3 5 7
隸屬關係
隸屬關係

    1
    德國漢諾威漢諾威醫學院胃腸病學、肝病學和內分泌學系。
    2
    TWINCORE 實驗和臨床感染研究中心，德國漢諾威。
    3
    德國感染研究中心 (Deutsches Zentrum für Infektionsforschung DZIF)，合作夥伴站點 Hannover-Braunschweig，德國漢諾威。
    4
    個體化醫學的計算生物學，亥姆霍茲感染研究中心 (HZI)，轉交 CRC，漢諾威，德國。
    5
    個體化感染醫學中心 (CiiM)，轉交 CRC，漢諾威，德國。
    6
    德國漢諾威漢諾威醫學院胃腸病學、肝病學和內分泌學系[email protected]。
    7
    德國漢諾威漢諾威醫學院解決感染易感性卓越集群 (RESIST; EXC 2155)。

    PMID：34702717 DOI：10.1136/gutjnl-2021-324646

抽象的

目的：乙型肝炎病毒 (HBV) 特異性 T 細胞是控制 HBV 感染的主要效應細胞，乙型肝炎表面抗原 (HBsAg) 被認為是免疫反應受損的關鍵因素，是慢性 HBV 感染的標誌。除了 HBsAg 之外，還有其他病毒標誌物，如乙型肝炎核心相關抗原 (HBcrAg)，但它們與 HBV 特異性免疫反應的潛在關聯尚未確定，如果這些標誌物用於患者分層，這將很重要旨在功能性 HBV 治癒的新療法。

設計：我們分析了 92 名具有不同 HBsAg 和 HBcrAg 水平的乙型肝炎 e 抗原陰性慢性 HBV 感染患者的 T 細胞反應。重疊肽用於體外反應分析 (n=57)，並在人類白細胞抗原 (HLA)-A*02 患者 (n=35) 中評估了 HBV core18 特異性和聚合酶 (pol)455 特異性 CD8+ T 細胞.此外，還研究了對抗程序性細胞死亡配體 1（抗 PD-L1）的體外反應性。

結果：HBV 特異性 T 細胞反應不受 HBsAg 水平的影響，而是受年齡和 CD4+ T 細胞反應在 HBcrAg 水平低的患者中最高。 HBV core18 特異性和 pol455 特異性 CD8+ T 細胞的表型和功能不同，但 HBsAg 和 HBcrAg 水平不影響它們的特徵。用抗 PD-L1 阻斷可以恢復 HBV 特異性 T 細胞，但在從低 HBsAg 尤其是低 HBcrAg 患者中分離的 T 細胞中效果顯著更高。

結論：我們的數據表明年齡和 HBcrAg 而不是 HBsAg，與 HBV 特異性 T 細胞反應相關。最後，HBsAg，特別是 HBcrAg 表明的非常低的抗原水平可能會影響 T 細胞對檢查點抑制的反應。

關鍵詞：T淋巴細胞；細胞免疫學；慢性肝炎；乙型肝炎;免疫反應。

© 作者（或其雇主）2021 年。CC BY-NC 允許重複使用。沒有商業再利用。查看權利和權限。由 BMJ 出版。
利益衝突聲明

競爭利益：未聲明。

StephenW

Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection
Elmira Aliabadi  1   2   3 , Melanie Urbanek-Quaing  1   2   3 , Benjamin Maasoumy  1   3 , Birgit Bremer  1 , Martin Grasshoff  4 , Yang Li  2   4   5 , Christian E Niehaus  1   2 , Heiner Wedemeyer  1   3 , Anke R M Kraft  1   2   3 , Markus Cornberg  6   2   3   5   7
Affiliations
Affiliations

    1
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
    2
    TWINCORE Center of Experimental and Clinical Infection Research, Hannover, Germany.
    3
    German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany.
    4
    Computational Biology for Individualised Medicine, Helmholtz Centre for Infection Research (HZI), c/o CRC, Hannover, Germany.
    5
    Centre for Individualized Infection Medicine (CiiM), c/o CRC, Hannover, Germany.
    6
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany [email protected].
    7
    Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC 2155), Hannover Medical School, Hannover, Germany.

    PMID: 34702717 DOI: 10.1136/gutjnl-2021-324646

Abstract

Objective: Hepatitis B virus (HBV)-specific T cells are main effector cells in the control of HBV infection and hepatitis B surface antigen (HBsAg) is suggested to be a critical factor in the impaired immune response, a hallmark of chronic HBV infection. In addition to HBsAg, other viral markers such as hepatitis B core-related antigen (HBcrAg) are available, but their potential association with HBV-specific immune responses is not defined yet, which will be important if these markers are used for patient stratification for novel therapies aimed at functional HBV cure.

Design: We analysed T cell responses in 92 patients with hepatitis B e antigen negative chronic HBV infection with different HBsAg and HBcrAg levels. Overlapping peptides were used for in vitro response analyses (n=57), and HBV core18-specific and polymerase (pol)455-specific CD8+ T cells were assessed in human leukocyte antigen (HLA)-A*02 patients (n=35). In addition, in vitro responsiveness to anti-programmed cell death-ligand 1 (anti-PD-L1) was investigated.

Results: HBV-specific T cell responses were not affected by HBsAg levels, but rather by age and CD4+ T cell responses were highest in patients with low HBcrAg levels. The phenotypes and functionality of HBV core18-specific and pol455-specific CD8+ T cells differed, but HBsAg and HBcrAg levels did not affect their profiles. Blocking with anti-PD-L1 could restore HBV-specific T cells, but the effect was significantly higher in T cells isolated from patients with low HBsAg and in particular low HBcrAg.

Conclusion: Our data suggest that age and HBcrAg rather than HBsAg, are associated with HBV-specific T cell responses. Finally, very low antigen levels indicated by HBsAg and in particular HBcrAg may influence T cell response to checkpoint inhibition.

Keywords: T lymphocytes; cellular immunology; chronic hepatitis; hepatitis B; immune response.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Conflict of interest statement

Competing interests: None declared.

StephenW

https://gut.bmj.com/content/gutj ... 021-324646.full.pdf