Spontaneous or treatment induced seroconversion in chronic HBV infection is rare and generation of anti-HBs antibodies is the current goal of HBV therapeutics. Here we investigated B and follicular T helper (Tfh) cell defects that persist in HBV infection despite long-term nucleos(t)ide analog (NUC) treatment and possible mechanisms behind them. RNA sequencing revealed that patient B cells have upregulated expression of multiple inhibitory receptors including members of FcRL family and downregulation of genes involved in antigen presentation. An expansion of atypical memory CD19⁺CD10^-CD27^-CD21^- subset of B cells, that express high levels of FcRL5, is persistently present in patients. HBs antigen specific IgG response is concentrated in classical memory and not in atypical memory subset, confirming dysfunction of this subset. Activated Tfh, which expressed excessive CD40L upon polyclonal stimulation, were present in patients. Incubation of B cells from healthy individuals with HBV core (HBc) or CD40L resulted in induction of inhibitory receptors FcRL4, FcRL5 and PD-1 on CD19+ cells and resulted in altered B cell phenotypes. Mechanistically, HBc binds B cells and causes proliferation specifically of FcRL5+ B cell subset. Our results provide evidence that HBV directly causes upregulation of inhibitory pathways in B cells resulting in an accumulation of atypical B cells that lack anti-HBs function.

中文翻译：

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HBV诱导B细胞上的抑制性FcRL受体，并异常调节B细胞-T滤泡辅助细胞轴。

慢性HBV感染中自发或由治疗引起的血清转化很少见，抗HBs抗体的产生是HBV治疗剂的当前目标。在这里，我们研究了尽管长期进行核苷酸（t）ide类似物（NUC）治疗后仍持续存在于HBV感染中的B和滤泡T辅助（Tfh）细胞缺陷及其背后的可能机制。RNA测序显示，患者B细胞的多种抑制性受体（包括FcRL家族成员）的表达上调，而与抗原呈递有关的基因则下调。非典型存储器CD19的膨胀⁺ CD10 ^- CD27 ^- CD21 ^-患者中持续存在表达高水平FcRL5的B细胞亚群。HBs抗原特异性IgG应答集中在经典记忆中，而不是在非典型记忆子集中，这证实了该子集的功能障碍。患者中存在活化的Tfh，其在多克隆刺激后表达过量的CD40L。将健康人的B细胞与HBV核心（HBc）或CD40L一起温育导致诱导CD19 +细胞上的抑制性受体FcRL4，FcRL5和PD-1，并导致B细胞表型改变。从机理上讲，HBc结合B细胞并引起FcRL5 + B细胞亚群的特异性增殖。我们的结果提供了证据，表明HBV直接导致B细胞中抑制途径的上调，导致缺乏抗HBs功能的非典型B细胞积聚。