IL-4R+SELL+ Naïve B Cell Expansion correlates with functional cure in PEG-IFNα Treated Chronic Hepatitis B Patients

During chronic hepatitis B (CHB) infection, B cell dysfunction is a key contributor to viral persistence. Pegylated interferon alpha (PEG-IFNα) acts as an effective therapeutic agent for CHB by restoring immune responses directed against HBV, however, a comprehensive landscape of the B-cell responses associated with functional cure has not been fully elucidated. In this study, we employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to quantitatively assess the B-cell subsets in nucleos(t)ide analog (NAs)-treated CHB patients receiving sequential PEG-IFNα add-on therapy. We identified two functionally distinct naïve B cell subsets (IL-4R + SELL + and IL-4R-SELL-) and three memory B cell populations in peripheral blood. Patients who achieved a functional cure displayed significantly elevated frequencies of total B cells and the IL-4R + SELL + naïve B cell subset, whereas memory B cell frequencies remained comparable between groups. In contrast to cured patients, uncured individuals exhibited sustained activation of type I interferon response pathways in both naive and memory B cells, which may be a key mechanism of B cell dysfunction. Notably, the frequency of IL-4R + SELL + naïve B cells during the treatment was inversely correlated with baseline HBsAg levels at the initiation of PEG-IFNα therapy, and has high predictive value for HBsAg loss following PEG-IFNα therapy. Our results indicate that CHB patients attaining functional cure after PEG-IFNα add-on therapy undergo a distinct B cell reconstitution, characterized by a pronounced expansion of peripheral IL-4R + SELL + naïve B cells. This finding highlights its dual significance as both a novel immunological biomarker and a potential therapeutic target for CHB functional cure.