HBV induces inhibitory FcRL receptor on B cells and dysregulates B cell-T follicular helper cell axis

Abstract

Spontaneous or treatment induced seroconversion in chronic HBV infection is rare and generation of anti-HBs antibodies is the current goal of HBV therapeutics. Here we investigated B and follicular T helper (Tfh) cell defects that persist in HBV infection despite long-term nucleos(t)ide analog (NUC) treatment and possible mechanisms behind them. RNA sequencing revealed that patient B cells have upregulated expression of multiple inhibitory receptors including members of FcRL family and downregulation of genes involved in antigen presentation. An expansion of atypical memory CD19+CD10−CD27−CD21− subset of B cells, that express high levels of FcRL5, is persistently present in patients. HBs antigen specific IgG response is concentrated in classical memory and not in atypical memory subset, confirming dysfunction of this subset. Activated Tfh, which expressed excessive CD40L upon polyclonal stimulation, were present in patients. Incubation of B cells from healthy individuals with HBV core (HBc) or CD40L resulted in induction of inhibitory receptors FcRL4, FcRL5 and PD-1 on CD19+ cells and resulted in altered B cell phenotypes. Mechanistically, HBc binds B cells and causes proliferation specifically of FcRL5+ B cell subset. Our results provide evidence that HBV directly causes upregulation of inhibitory pathways in B cells resulting in an accumulation of atypical B cells that lack anti-HBs function.

Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV

“…The HBV capsid is known to be a remarkable immunogenic structure, 19,20 so it is puzzling why HBsAg-specific B cells responses are exhausted as suggested by recent studies, 7,8 but not HBcAg-specific B cells. Differences in antigen-specific follicular T cell help 6 or different degrees of antigen exposure are likely to contribute. While HBsAg is known to be secreted in high excess to HBV virions, the kinetics of HBV capsid expression and its presence in serum remain unclear.…”

“…[2][3][4][5] HBsAg B cell ELISPOT assays detect low numbers of anti-HBsAg-antibody (HBsAb)-producing B cells in the blood of patients with CHB, despite the presence of vast amounts of HBsAg in their serum. [4][5][6] Recently, HBsAg-specific B cells could be directly isolated ex vivo from the liver and blood of patients with CHB by using fluorescently labeled HBsAg as baits. 7,8 These HBsAg-specific cells had an impaired anti-HBs antibody production capacity and were enriched for an atypical memory (ATM) B cell phenotype, expressing low levels of both the classical human memory B cell marker CD27 and complement receptor CD21, and high levels of co-inhibitory markers, such as PD-1 and FcRL5, 7,8 suggesting that the HBsAg-specific B cells are exhausted.…”

Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection

“…To help characterize the B lymphocyte population in this cohort, we looked at the activation markers CD69, CD95, and HLA-DR. Fc receptor-like 4 (FCRL4) was also measured, as it is upregulated on B cells of lymphoid tissue, increased in the periphery during some chronic infections and autoimmune diseases, and is associated with an exhausted B-cell phenotype (37)(38)(39)(40)(41)(42). We also examined the frequencies of the exhaustion marker PD1, and the memory marker, (Figure 6A; p=0.052 and p=0.031, respectively).…”

Sustained Cellular Immune Dysregulation in Individuals Recovering from SARS-CoV-2 Infection

“…To help characterize the B lymphocyte population in this cohort, we looked at the activation markers CD69, CD95, and HLA-DR. Fc receptor-like 4 (FcRL4) was also measured, as it is upregulated on B cells of lymphoid tissue, increased in the periphery during some chronic infections and autoimmune diseases, and is associated with an exhausted B-cell phenotype (37)(38)(39)(40)(41)(42). We also examined the frequencies of the exhaustion marker PD1, and the memory marker,…”