Immune predictors of hepatitis B surface antigen seroconversion in patients with hepatitis B reactivation

Abstract

Background: Hepatitis B surface antigen (HBsAg) seroconversion is sometimes observed in hepatitis B reactivation (rHBV), probably due to immune resetting and differentiation.

Aims: To investigate sequential immune differentiation and abrogation of tolerance in patients with rHBV who achieved HBsAg seroconversion.

Methods: We included 19 patients with chronic hepatitis B (CHBV; HBV DNA log10^3-8 ), 67 with rHBV (raised ALT [>5XULN], HBV DNAlog10^4-8 ) and 10 healthy controls. Immune differentiation, tolerance and functional status of CD4, CD8, T regulatory cells (Tregs), B cells and follicular T helper (Tfh) cells were assessed at baseline and 24 weeks.

Results: At 24 weeks, 81% rHBV (n = 67) lost HBV DNA and HBeAg (41%), and 12 (19%) lost HBsAg and made anti-HBs titers >10 IU/ml. rHBV patients had higher Th1/17, T_EM , Tfh, Tfh1/17, plasma and ATM B cells, and lower Tregs, Th2, Th17 and TEMRA expression. rHBV showed lower PD1, TIM3, LAG3, SLAM and TOX compared to CHBV. There was a significant increase in CD8, CD8EM, Tfh, Tfh1/17 and plasma B cells in seroconverters than non-seroconverters. At 24 weeks, we also observed increased plasma B cell frequency in seroconverters. While non-seroconverters showed higher expression of PD1, TIM3, LAG3, SLAM and TOX on CD4/CD8 T cells, blockade of PD1, TIM3, LAG3 and CTLA4 significantly enhanced IFN-γ, TNF-α, IL-4 and IL-21 expression on CD4/CD8 and Tfh cells in non-seroconverters.

Conclusions: Non-seroconverters have increased inhibitory markers on CD4/CD8 T cells. There is a critical play of CD8, Tfh and B cells and subsets in seroclearance, along with checkpoint molecules as a potential therapy for non-seroconverters in HBV infection.

Keywords: HBV immunology; HBsAg seroconversion; chronic hepatitis B; hepatitis B virus; reactivation of HBV; seroconversion.