Peripheral immune landscape in hepatitis B virus-related acute-on-chronic liver failure: Tumor necrosis factor-α, M1-like macrophages, and lymphocyte exhaustion

BACKGROUNDHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a critical illness with high 28-day mortality.It is associated with immunometabolic-mediated systemic inflammation leading to multi-organ failure. AIMTo investigate the peripheral immune landscape in patients with HBV-ACLF, with particular attention to the associations among tumor necrosis factor-alpha (TNF-α) levels, M1 macrophage polarization, and lymphocyte exhaustion. METHODSIn this prospective cross-sectional study of 97 subjects (healthy controls, chronic hepatitis B, and HBV-ACLF), flow cytometry and enzyme-linked immunosorbent assay quantified peripheral immune profiles and cytokines.Independent associated factors were identified via least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression.The Benjamini-Hochberg false discovery rate (FDR) correction was applied to all intergroup comparisons and correlation analyses. RESULTSHBV-ACLF patients exhibited profound peripheral immune remodeling, featuring a pro-inflammatory shift toward M1-like monocyte/macrophage polarization accompanied by compensatory upregulation of M2-like monocytes/macrophages and a sharp escalation in serum TNF-α, interferon-gamma, and interleukin (IL)-6 (all FDRadjusted P < 0.05).LASSO regression with 10-fold cross-validation selected 9 feature variables, and after iterative variance inflation factor refinement, 6 variables were 4 / 47 retained.Firth's bias-reduced logistic regression identified elevated TNF-α as an independent associated factor [odds ratio (OR) = 1.359, 95%CI: 1.056-1.749,P = 0.017].Notably, TNF-α and IL-6 exhibited strong collinearity (Spearman rho = 0.834); sensitivity analysis substituting IL-6 for TNF-α yielded consistent findings (IL-6: OR = 1.187, 95%CI: 1.052-1.339,P = 0.005).Stratified and correlation analyses revealed that high TNF-α and M1-like monocyte/macrophage polarization positively correlated with clinical severity (total bilirubin, creatinine) and negatively with lymphocyte percentages, while M2-like monocytes/macrophages positively correlated with neutrophil ratio (FDR-adjusted P < 0.05).Staging analysis showed a synchronized TNFα surge, M1 shift, and deep lymphocyte depletion during mid-to-late stages (prothrombin activity ≤ 30%). CONCLUSIONThis study systematically characterized the coexistence of pro-inflammatory remodeling and immune exhaustion within the peripheral immune landscape of HBV-ACLF, identifying TNF-α as a key immunopathological associated factor.These findings highlight the potential value of targeting TNF-α and monitoring multi-lineage immune crosstalk for risk stratification and therapeutic intervention in HBV-ACLF.