Differential Methylation Patterns Predict HBsAg Seroconversion in Hepatitis B Virus Reactivation Patients.

BACKGROUND

Hepatitis B virus (HBV) modulates immune epigenetic landscape. Therefore, we investigated immune epigenetic landscape in HBsAg seroconverters and non-seroconverters.

METHODS

Sixteen rHBV patients including seroconverters (SC, n = 7) and non-seroconverters (NSC, n = 9) at baseline and week 24 were recruited. Age matched naïve chronic hepatitis B patients (nCHBV, n = 7) and healthy controls (HC, n = 6) were also included. PBMCs and plasma were subjected to genome-methylation, gene-expression, immunophenotyping, functionality, and cytokines analysis using Reduced Representation Bisulfite Sequencing (RRBS), qRT-PCR, flow-cytometry, and cytokine-bead-array.

RESULTS

In rHBV patients, as compared to nCHBV, there is significant hypomethylation (p < .05) of epigenetic remodellers and immune and metabolic genes like KDM2B, NCOR2 and GATA6, TGF-β, IL-6, IRF8, RPTOR, HK3, specifically at CpG islands. At baseline, HBsAg SC had hypomethylation of KDM2B, COX19, IRF8, TLR5, and hypermethylation of LAG3 compare to NSC. By week-24, SC demonstrated hypomethylation of IL17RA, IFN-γ, TGF-β, STAT5B (p < .05) and correlated with increased plasma IL-6 (p = .009) and decreased LAG3 (p = .01). At baseline and 24 weeks, SC depicted differentiation of HBV-specific CD8+, Tfh, and Th1/17 cells.

CONCLUSION

This study identifies hypomethylation of immune genes suggesting enhanced immune response and viral clearance in SC. Conversely, nCHBV and NSC consistently exhibited hypomethylation of LAG3 and TOX, contributing to immune exhaustion.