慢性乙型肝炎患者功能障碍的CD56-CD16 + NK细胞的扩增

StephenW

Expansion of dysfunctional CD56-CD16+ NK cells in chronic hepatitis B patients
Ratna S Wijaya  1   2 , Scott A Read  1   3 , Stephen Schibeci  1 , Shuanglin Han  1 , Mahmoud K Azardaryany  1 , David van der Poorten  4 , Rita Lin  4 , Lawrence Yuen  4   5 , Vincent Lam  4   5 , Mark W Douglas  1   4   6 , Jacob George  1   4 , Golo Ahlenstiel  1   3   7
Affiliations
Affiliations

    1
    Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, 2145, Australia.
    2
    Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia.
    3
    Blacktown Clinical School, Western Sydney University, Blacktown, NSW, 2148, Australia.
    4
    Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
    5
    Discipline of Surgery, University of Sydney, Sydney, Australia.
    6
    Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia.
    7
    Blacktown Hospital, Blacktown, NSW, 2148, Australia.

    PMID: 33411395 DOI: 10.1111/liv.14784

Abstract

Background & aims: Natural killer (NK) cells are primary innate effector cells that play an important role in the control of human viral infections. During chronic viral infection, NK cells undergo significant changes in phenotype, function, and subset distribution, including the appearance of CD56-CD16+ (CD56-) NK cells, previously identified in chronic human immunodeficiency virus (HIV) and hepatitis C virus infection. However, the presence of CD56- NK cells in the pathogenesis of chronic hepatitis B (CHB) remains unknown.

Methods: Phenotype and function of CD56- NK cells from patients with CHB (n=28) were assessed using flow cytometry and in vitro stimulation with HBV antigen.

Results: CHB patients had a higher frequency of CD56- NK cells compared to healthy controls in peripheral blood (6.2 vs 1.4%, p<0.0001). Compared to CD56+ NK cells, CD56- NK cells had increased expression of inhibitory receptors, and reduced expression of activating receptors, as measured by MFI and qPCR. CD56- NK cells were less responsive to target cell and cytokine stimulation compared to their CD56+ counterparts. In addition, CD56- NK cells demonstrated defective dendritic cells (DCs) interactions resulting in reduced DCs maturation, lower expression of NK CD69, and impaired capacity of NK cells to eliminate immature DCs in co-culture studies. Finally, frequency of CD56- NK cells was positively correlated with serum HBV DNA levels.

Conclusion: Chronic HBV infection induces the expansion of highly dysfunctional of CD56- NK cells that likely contribute to inefficient innate and adaptive antiviral immune response in chronic HBV infection.

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StephenW

慢性乙型肝炎患者功能障碍的CD56-CD16 + NK细胞的扩增
Ratna S Wijaya 1 2，Scott A Read 1 3，Stephen Schibeci 1，Shuanglin Han 1，Mahmoud K Azardaryany 1，David van der Poorten 4，Rita Lin 4，Lawrence Yuen 4 5，Vincent Lam 4 5，Mark W Douglas 1 4 6，雅各布·乔治1 4，戈洛·阿伦斯蒂尔1 3 7
隶属关系
隶属关系

    1个
    澳大利亚新南威尔士州韦斯特米德，悉尼大学，韦斯特米德医学研究所斯托肝中心，澳大利亚，2145。
    2
    印度尼西亚坦格朗Pelita Harapan大学医学院。
    3
    澳大利亚新南威尔士州布莱克敦，西悉尼大学布莱克敦临床学校，澳大利亚2148。
    4
    澳大利亚新南威尔士州悉尼大学，韦斯特米德医院。
    5
    悉尼大学外科学科，澳大利亚悉尼。
    6
    悉尼大学玛丽分校传染病与生物安全研究所传染病和微生物学中心，悉尼，新南威尔士州韦斯特米德，西密德医院，澳大利亚2145。
    7
    澳大利亚新南威尔士州布莱克敦，布莱克敦医院，2148，澳大利亚。

    PMID：33411395 DOI：10.1111 / liv.14784

抽象

背景与目的：自然杀伤（NK）细胞是主要的先天效应细胞，在控制人类病毒感染中起着重要作用。在慢性病毒感染期间，NK细胞的表型，功能和子集分布发生重大变化，包括先前在慢性人免疫缺陷病毒（HIV）和丙型肝炎病毒感染中鉴定出的CD56-CD16 +（CD56-）NK细胞的出现。但是，CD56-NK细胞在慢性乙型肝炎（CHB）发病机理中的存在仍然未知。

方法：采用流式细胞仪和HBV抗原体外刺激，评估CHB患者（n = 28）CD56-NK细胞的表型和功能。

结果：与健康人外周血相比，CHB患者的CD56-NK细胞频率更高（6.2％vs 1.4％，p <0.0001）。与CD56 + NK细胞相比，CD56-NK细胞的抑制受体表达增加，而活化受体的表达减少，如MFI和qPCR所测量的。与CD56 +对应物相比，CD56-NK细胞对靶细胞和细胞因子刺激的反应较弱。另外，在共培养研究中，CD56-NK细胞表现出缺陷的树突状细胞（DC）相互作用，导致DC的成熟度降低，NK CD69的表达降低以及NK细胞消除未成熟DC的能力受损。最后，CD56-NK细胞的频率与血清HBV DNA水平呈正相关。

结论：慢性HBV感染可诱导高度功能障碍的CD56-NK细胞扩增，这可能导致慢性HBV感染无效的先天性和适应性抗病毒免疫反应。

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