A genomic and transcriptomic integration study of CCL19-driven macrophage-immune crosstalk in chronic hepatitis B.

Chronic hepatitis B (CHB) progression features stage-dependent immune dysfunction, transitioning from high viremia in immune-tolerant phases to persistent liver injury during immune activity. While inflammatory mediators facilitate hepatitis B virus (HBV) persistence and hepatocyte damage, their causal orchestration remains undefined. This multi-omics investigation systematically identifies inflammation-related therapeutic targets through causal inference analysis of CHB pathogenesis. We conducted two-sample Mendelian randomization (TSMR) analysis to investigate causal associations with circulatory inflammatory mediators. Subsequent integrative multi-omics investigations incorporated single-cell transcriptomic profiling (GSE186343 and GSE182159) and bulk tissue sequencing data (GSE65359 and GSE83148). Single-cell data processing involved Seurat pipelines with Harmony batch correction. Transcriptomic alterations were systematically characterized using limma-based differential analysis coupled with CIBERSORT-mediated immune composition deconvolution. Molecular networks were established through pySCENIC transcriptional regulation modeling, cellular differentiation patterns were resolved via Monocle2 trajectory inference, and ligand-receptor dynamics were examined using CellChat/NicheNet frameworks. Therapeutic compound identification was achieved through computational screening of CMAP pharmacogenomic signatures. This investigation applied TSMR to pinpoint CCL19 as a principal mediator among 91 circulatory inflammatory proteins exhibiting causal positivity in CHB pathogenesis. Mechanistic multi-omics integration delineated its immunomodulatory pathways. Genomic epidemiology demonstrated that heightened circulating CCL19 concentrations substantially elevate hepatitis B viral susceptibility. Single-cell resolution profiling revealed CCL19 spatial enrichment specifically within antigen-presenting macrophage clusters (M4 phenotype) in CHB hepatic microenvironments. Functional coordination was observed with pro-inflammatory cytotoxic macrophage populations (M3 phenotype) through IFNG and HLA signaling crosstalk, simultaneously potentiating antiviral defense mechanisms and inflammatory tissue damage. Subsequently, we postulated a transcriptional regulatory cascade involving RB1, MEF2A, and SEMA4A that may control CCL19 expression. The investigation demonstrated a dysregulation in the balance of macrophage and T cell subsets among CHB patients, while pinpointing CCL19 as a critical macrophage-derived biomarker. This chemokine’s upregulated expression may exhibit significant correlations with amplified chemotactic signaling and engagement of the antigen processing/presentation cascade.