Single‐Cell Profiling of Peripheral and Intrahepatic B Cells Reveals Altered Responses and a CCR7⁺ Subset Linked to Antiviral Potential in Chronic HBV Infection

ABSTRACT B cell is a crucial component of adaptive immunity that plays a paramount role in the progression and prognosis of chronic hepatitis B virus (HBV) infection. However, detailed and systematic overviews of B cells are lacking, hindering their clinical applications in fighting against HBV. This study aims to provide a landscape of B cell responses in the context of chronic HBV infection. The phenotype, function, and transcriptome features of the peripheral and intrahepatic B cells in cross‐sectional and longitudinal cohorts of patients with chronic HBV infection were characterized using single‐cell RNA sequencing analysis coupled with flow cytometry. B cells displayed varying degrees of altered function at different natural stages of chronic HBV infection, as evidenced by their inhibitory phenotype, reduced B cell receptor (BCR) signaling, resulting in decreased production of antiviral cytokines, attenuated differentiation into memory B cells, weakened interactions with T cells. Additionally, in patients with chronic HBV infection, intrahepatic B cells exhibited augmented BCR signaling, cytokine secretion, differentiation, and intensified interactions with other immune cells, compared to their peripheral counterparts. It is noteworthy that CCR7 + B cells, characterized by high expression of activation markers and IL‐6, exhibited enhanced survival capacity and were elevated in treatment‐responsive patients. Our study provides a detailed insight into the B cell response in chronic HBV infection and highlights the potential clinical application of CCR7‐expressing B cell‐oriented anti‐HBV therapy.