Patients with chronic hepatitis B who lose the hepatitis B surface antigen, or HBsAg, while on combination therapy show a distinctive pattern of immune change, according to a new study published in BMC Immunology. The research tracked natural killer cell subsets and circulating cytokines in 27 patients treated with pegylated interferon-alpha together with nucleos(t)ide analogs, and found that those who achieved on-treatment HBsAg loss by week 48 differed measurably from those who did not.
The study set out to characterize how NK cell phenotypes, receptor expression and cytokine profiles change during this combination regimen and how those changes relate to clinical outcomes. HBsAg loss remains a major challenge in chronic hepatitis B, and identifying immune signatures associated with treatment response could help clarify the mechanisms behind successful therapy.
The 27 participants were stratified into two groups at week 48: an on-treatment HBsAg loss group, defined as HBsAg below 0.05 IU/mL, comprising 10 patients, and a non-HBsAg loss group of 17 patients. Flow cytometry was used to assess NK cell subsets, distinguishing CD56bright from CD56dim cells, and to measure expression of the receptors NKG2D, NKp30, NKp46, KIR, NKG2A and TIM3. Serum levels of the cytokines IFN-γ, TNF-α, IL-2, IL-4, IL-6 and IL-10 were measured by ELISA, and the researchers analyzed correlations between virological markers and NK cell subsets, receptors or cytokines.
Across both groups, the combination therapy expanded CD56bright NK cells while reducing CD56dim subsets.
The groups diverged in receptor expression. In the on-treatment HBsAg loss group, the researchers observed persistent upregulation of KIR, the killer cell immunoglobulin-like receptor, on CD56bright NK cells. At the same time, CD56dim NK cells in that group maintained elevated expression of NKG2A, a receptor that modulates NK cell activity.
Cytokine patterns also separated the two groups. Patients in the on-treatment HBsAg loss group showed significantly lower serum levels of the pro-inflammatory cytokines IFN-γ, TNF-α, IL-6 and IL-2, while maintaining higher levels of the anti-inflammatory cytokine IL-10. This combination of dampened inflammatory signaling and preserved anti-inflammatory activity characterized the group that achieved HBsAg loss.
Correlation analysis added another layer. In the on-treatment HBsAg loss group, HBsAg levels showed significant inverse correlations with the proportion of CD56bright NK cells and with receptor expression. In the same group, HBsAg correlated positively with CD56dim NK cell frequency. In both treatment groups, HBsAg was positively correlated with pro-inflammatory cytokine levels, linking viral antigen burden to inflammatory cytokine output.
The authors conclude that PEG-IFNα and NAs combination therapy is associated with on-treatment HBsAg loss at week 48, potentially through optimizing cytokine responses, regulating the CD56bright to CD56dim NK cell balance and modulating the related receptors. The study notes limitations including its single-center design and moderate sample size, and the findings are observational associations rather than proof of causation. The work was registered in a national medical research registry under the title Prediction of clinical curative effect of pegylated interferon a individualized intermittent treatment of nucleoside (acid) in patients with hepatitis B, with registration number MR-53-26-076931, dated 31 August 2026.
The study was published as open access on 12 October 2026, and the article version shared at publication is citable and carries a permanent DOI, subject to further edits before the final version of record appears.
Subject of Research: NK cell subset and cytokine changes during pegylated interferon-alpha and nucleos(t)ide analog combination therapy in chronic hepatitis B
Article Title: NK cell reconfiguration and cytokine dynamics during pegylated interferon-α and nucleos(t)ide analogs combination therapy in chronic hepatitis B
Article References: Li, C., Liu, X., Gong, M., Wu, C., Li, X., Zhou, T., Wei, J., & Li, H. (2026). NK cell reconfiguration and cytokine dynamics during pegylated interferon-α and nucleos(t)ide analogs combination therapy in chronic hepatitis B. BMC Immunology. https://doi.org/10.1186/s12865-026-00916-7
Image Credits: AI Generated
DOI: 10.1186/s12865-026-00916-7
Keywords: chronic hepatitis B, HBsAg loss, natural killer cells, pegylated interferon-alpha, nucleos(t)ide analogs, cytokines, CD56bright, CD56dim, NKG2A, KIR, immune response, BMC Immunology
News Source: Kristina Jarvis. (October 28, 2026). Immune cell shifts track hepatitis B treatment response. Scienmag.
