Immune correlates of hepatitis B surface antigen spontaneous seroconversion in hepatitis B e antigen negative chronic hepatitis B patients

Background Hepatitis B surface antigen ( HB sAg) seroconversion in HB eAg −ve chronic hepatitis B ( CHB ) infection is rare, possibly due to poor antigen processing and impaired humoral response. We investigated the role of dendritic cells ( DC s), T follicular helper ( TFH ) cells and plasma B cells in seroconversion. Methods HB eAg −ve (n=135) CHB patients with raised ALT at baseline were followed up. Patients undergoing HB sAg seroconversion (Gr. I, n=11) were compared with non‐converters with low (Gr. II , n=17, HBV DNA <2000 IU /mL) or high HBV DNA (Gr. III , HBV DNA >2000 IU /mL, n=17). We measured cell phenotypes ( TFH , B and DC s), HBV specific T‐cell functionality [using pooled overlapping surface and core peptides], IL 21 levels and gene expression analysis by qRT ‐ PCR . Results Patients in Gr. I compared to Gr. II and III , had higher IL ‐21 levels (865 vs 276 vs 111 pg/ mL , P =<.0001), TFH ( CD 4 + CXCR 5 + ) cells (12.3 vs 4.67 vs 2.77, P =<.001), inducible T‐cell co‐stimulator ( ICOS ) expression on TFH cells (20.0 vs 13.0 vs 13.68, P =.01), HB sAg specific IL ‐17 (9.40 vs 2.33 vs 2.61, P =<.001) and TNF ‐α secreting TFH 17 cells (82 vs 1.43 vs 2.33, P =<.001), plasma B ( CD 19 + CD 38 + ) cells (15.0 vs 5.08 vs 5.57, P =<.001), myeloid (17.80 vs 5.39 vs 2.70, P =<.001) and plasmocytoid DC s (2.6 vs 0.43 vs 0.21, P =<.001). Plasma B‐cell frequency ( R 2 =.64, P =.01) and IL ‐21 levels ( R 2 =.52, P =.003) correlated with anti‐ HB s titres in patients with HB sAg seroconversion. Conclusions Dendritic cell and TFH cell mediated responses regulate humoral responses against HBV and play a major role in HB sAg seroconversion in CHB patients.