Journal of clinical and translational hepatology · 2026
High Frequency of Circulating IL-4R+SELL+ Naïve B Cells Is Associated with Functional Cure in Chronic Hepatitis B Patients Receiving Antiviral Treatment.
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Tang Lili, Bao Chunmei, Zhen Cheng, Wang Huan, Zhang Chao, Zhang Yang, Liu Honghong, Song Jinwen, Jiao Yanmei, Yang Tao, Yuan Yue, Yuan Jinhong, Gao Yingying, Chen Yangliu, Cao Lin, Li Jing, Fu Jun-Liang, Wang Fu-Sheng, Xu Ruonan
Аннотация
BACKGROUND AND AIMS: Although hepatitis B surface antigen (HBsAg)-specific B cells have been partially characterized in chronic hepatitis B (CHB), the role of naïve B cells and their potential relevance to functional cure remain insufficiently explored. Here, we aimed to characterize the naïve B-cell subsets in functionally cured and uncured patients with CHB.
METHODS: In this retrospective study, we applied single-cell RNA sequencing to compare peripheral B-cell profiles in functionally cured and uncured CHB patients. Key findings were validated by flow cytometry in an independent cohort and further supported in a nucleos(t)ide analog monotherapy cohort stratified by HBsAg levels.
RESULTS: Single-cell RNA sequencing characterized two naïve B-cell subsets, designated IL-4R+SELL+ and IL-4R-SELL- naïve B cells, which were differentially distributed between functionally cured and uncured patients. Functionally cured patients showed higher frequencies of total B cells and IL-4R+SELL+ naïve B cells than uncured patients. In contrast, functionally uncured patients exhibited persistent hyperactivation of type I interferon signaling in both naïve and memory B cells. The IL-4R+SELL+ subset showed a transcriptional signature associated with germinal center biology and exhibited stronger ligand-receptor interactions with CD40LG+CD4+ T cells. Notably, the frequency of the IL-4R+SELL+ subset was inversely correlated with HBsAg levels. Consistently, patients with lower HBsAg levels also exhibited significantly higher frequencies of IL-4R+SELL+ naïve B cells compared with those with high HBsAg levels.
CONCLUSIONS: Collectively, these findings indicate that the IL-4R+SELL+ naïve B-cell subset is characterized by germinal center-related responses and enhanced T-cell-mediated help and may serve as an immunological component associated with functional cure in CHB.
METHODS: In this retrospective study, we applied single-cell RNA sequencing to compare peripheral B-cell profiles in functionally cured and uncured CHB patients. Key findings were validated by flow cytometry in an independent cohort and further supported in a nucleos(t)ide analog monotherapy cohort stratified by HBsAg levels.
RESULTS: Single-cell RNA sequencing characterized two naïve B-cell subsets, designated IL-4R+SELL+ and IL-4R-SELL- naïve B cells, which were differentially distributed between functionally cured and uncured patients. Functionally cured patients showed higher frequencies of total B cells and IL-4R+SELL+ naïve B cells than uncured patients. In contrast, functionally uncured patients exhibited persistent hyperactivation of type I interferon signaling in both naïve and memory B cells. The IL-4R+SELL+ subset showed a transcriptional signature associated with germinal center biology and exhibited stronger ligand-receptor interactions with CD40LG+CD4+ T cells. Notably, the frequency of the IL-4R+SELL+ subset was inversely correlated with HBsAg levels. Consistently, patients with lower HBsAg levels also exhibited significantly higher frequencies of IL-4R+SELL+ naïve B cells compared with those with high HBsAg levels.
CONCLUSIONS: Collectively, these findings indicate that the IL-4R+SELL+ naïve B-cell subset is characterized by germinal center-related responses and enhanced T-cell-mediated help and may serve as an immunological component associated with functional cure in CHB.