High Frequency of Circulating IL-4R+SELL+ Naïve B Cells Is Associated with Functional Cure in Chronic Hepatitis B Patients Receiving Antiviral Treatment.

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.