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

BackgroundHepatitis B surface antigen (HBsAg) seroconversion in HBeAg -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 (DCs), T follicular helper (TFH) cells and plasma B cells in seroconversion. MethodsHBeAg -ve (n=135) CHB patients with raised ALT at baseline were followed up. Patients undergoing HBsAg 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 DCs), HBV specific T-cell functionality [using pooled overlapping surface and core peptides], IL21 levels and gene expression analysis by qRT-PCR. ResultsPatients in Gr. I compared to Gr. II and III, had higher IL-21 levels (865 vs 276 vs 111pg/mL, P=<.0001), TFH (CD4(+)CXCR5(+)) 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), HBsAg specific IL-17 (9.40 vs 2.33 vs 2.61, P=<.001) and TNF- secreting TFH17 cells (82 vs 1.43 vs 2.33, P=<.001), plasma B (CD19(+)CD38(+)) cells (15.0 vs 5.08 vs 5.57, P=<.001), myeloid (17.80 vs 5.39 vs 2.70, P=<.001) and plasmocytoid DCs (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-HBs titres in patients with HBsAg seroconversion. ConclusionsDendritic cell and TFH cell mediated responses regulate humoral responses against HBV and play a major role in HBsAg seroconversion in CHB patients.