慢性乙型肝炎患者的乙肝核心特异性记忆B细胞反应与临床参

StephenW

Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV

    Thomas Vanwolleghem
    Zwier M.A. Groothuismink
    Kim Kreefft
    Magdeleine Hung
    Nikolai Novikov
    Andre Boonstra

Published:February 12, 2020DOI:https://doi.org/10.1016/j.jhep.2020.01.024

Highlights

    •
    B cell responses in chronic HBV are predominantly directed against HBcAg, not HBsAg.
    •
    HBcAg-specific memory B cells associate with HBV's clinical phases.
    •
    HBcAg-specific B cell responses are reduced during antiviral treatment.

Background & Aims
Little is known about the frequency, phenotype and function of HBV-specific B cells during chronic infection. Here we study HBcAg and HBsAg-specific B cells in different clinical phases of a chronic HBV infection.
Methods
We included 118 treatment naïve and 34 nucleos(t)ide analogue-treated patients with chronic HBV and 23 healthy HBsAg-vaccinated controls. Global and HBV-specific B lymphocytes were examined by FACS using fluorescently labeled HBsAg and HBcAg as baits. Functional HBV-specific B cell responses were quantified in B cell ELISPOT assays. Anti-HBs and anti-HBc antibodies were measured in serum and in ELISPOT supernatant by ELISA.
Results
Higher HBcAg-directed B cell responses were found in HBV clinical phases with elevated vs. low serum alanine aminotransferase (ALT) levels, irrespective of the HBeAg-status. In contrast, HBsAg-directed responses were lower and did not significantly fluctuate. In individual patients a mean 17.8-fold more circulating B cells target HBcAg than HBsAg baits. These HBcAg-specific B cells present a classical memory B cell profile and have slightly higher CD69 expression levels compared to global memory B cells. Viral suppression and ALT normalization upon treatment led to a numeric and functional reduction of HBcAg-specific B cell responses, accompanied by progressive decreases in serum anti-HBc antibodies.
Conclusion
HBcAg-specific memory B cells present a classical memory B cell phenotype, vary in number and function throughout HBV's natural history and are significantly reduced during antiviral treatment.
Lay summary
In recent years, studies examining the role of B cells during chronic hepatitis B virus infection have regained interest. We show that circulating B cells more often target the hepatitis B core antigen than the hepatitis surface antigen. Moreover, these hepatitis B core-specific B cells associate with the natural history of chronic HBV, and their responses decline during effective antiviral treatment.

StephenW

慢性乙型肝炎患者的乙肝核心特异性记忆B细胞反应与临床参数相关

    托马斯·范沃尔莱格姆
    Zwier M.A. Groothuismink
    金·克里夫特
    洪宝莲
    尼古拉·诺维科夫（Nikolai Novikov）
    安德烈·邦斯特拉（Andre Boonstra）

发布时间：2020年2月12日DOI：https：//doi.org/10.1016/j.jhep.2020.01.024

强调

    •
    慢性HBV中的B细胞反应主要针对HBcAg，而非HBsAg。
    •
    HBcAg特异性记忆B细胞与HBV的临床阶段有关。
    •
    抗病毒治疗期间HBcAg特异性B细胞反应降低。

背景与目标
关于慢性感染期间HBV特异性B细胞的频率，表型和功能知之甚少。在这里，我们研究慢性HBV感染的不同临床阶段中的HBcAg和HBsAg特异性B细胞。
方法
我们纳入了118例未经治疗的初治患者和34例经核苷酸（t）核苷酸类似物治疗的慢性HBV患者和23例健康的HBsAg疫苗接种对照。用荧光标记的HBsAg和HBcAg作为诱饵，通过FACS检查整体和HBV特异性B淋巴细胞。在B细胞ELISPOT分析中定量了功能性HBV特异性B细胞反应。通过ELISA测量血清和ELISPOT上清液中的抗-HBs和抗-HBc抗体。
结果
在HBV临床阶段，无论血清HBeAg的状态如何，血清丙氨酸转氨酶（ALT）水平相对较高或较低时，都存在较高的HBcAg定向B细胞应答。相反，针对HBsAg的反应较低，并且没有明显的波动。在个别患者中，靶向HBcAg的循环B细胞平均比HBsAg诱饵多17.8倍。与整体记忆B细胞相比，这些HBcAg特异性B细胞表现出经典的记忆B细胞特征，并具有略高的CD69表达水平。治疗后病毒抑制和ALT正常化导致HBcAg特异性B细胞反应的数量和功能降低，同时血清抗HBc抗体逐渐降低。
结论
HBcAg特异性记忆B细胞表现出经典的记忆B细胞表型，在整个HBV的自然病史中数量和功能均发生变化，并且在抗病毒治疗期间会显着降低。
放置摘要
近年来，研究B细胞在慢性乙型肝炎病毒感染中的作用的研究重新引起了人们的兴趣。我们显示，循环中的B细胞比肝炎表面抗原更常靶向乙肝核心抗原。此外，这些乙型肝炎核心特异性B细胞与慢性HBV的自然病史相关，在有效的抗病毒治疗期间其反应下降。

StephenW

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