Circulating and intrahepatic antiviral B cells are defective in hepatitis B

Abstract

B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21–CD27– atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1hiatMBC and impairing B cell immunity.

HBcAg‐induced upregulated 4‐1BB ligand on B cells contributes to B‐cell hyperactivation during chronic hepatitis B infection

“…Besides, although B cells had a higher 4‐1BBL expression in patients with CHB, and the 4‐1BBL+ B cells also expressed high levels of costimulatory molecules and could activate T cells in vitro. In the present study, the overall activation of T cells in patients with CHB was not observed, reflecting the dysfunction of B and T cells in antiviral immunity during chronic HBV infection …”

Single cell resolution landscape of equine peripheral blood mononuclear cells reveals diverse immune cell subtypes including T-bet+B cells

“…In mice, T-bet + B cells have been shown to be important for antiviral humoral immunity (34,62,63). In humans, T-bet + B cells have been detected in peripheral blood in a variety of chronic inflammatory contexts including systemic lupus erythematosus (64,65), chronic malaria exposure (66,67), and chronic viral infection (16,40,68). Although a universal definition and designated function for these cells remains elusive, T-bet + B cells are often classified as atypical memory B cells and, at least in some contexts, are thought to arise from repetitive BCR stimulation (17).…”

Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

“…64 Interestingly, a recent study indicated that PD-1 was also overexpressed in hepatitis B surface antigen (HBsAg)-specific B cells. 65,66 These HBsAg-specific B cells had a marked reduction of antibody production that could be partially revived by PD-1 blockade. 65,66 These findings suggest that the suppressive role of ICs may extend beyond virus-specific T cells to virus-specific B cells.…”

“…65,66 These HBsAg-specific B cells had a marked reduction of antibody production that could be partially revived by PD-1 blockade. 65,66 These findings suggest that the suppressive role of ICs may extend beyond virus-specific T cells to virus-specific B cells. Beyond PD-1 Recent studies indicate a critical role of TIGIT in chronic viral infections.…”