Circulating and intrahepatic antiviral B cells are defective in hepatitis B
Alice R. Burton, … , Nadege Pelletier, Mala K. Maini
Alice R. Burton, … , Nadege Pelletier, Mala K. Maini
Published August 9, 2018
Citation Information: J Clin Invest. 2018;128(10):4588-4603. https://doi.org/10.1172/JCI121960.
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Research Article Immunology Infectious disease

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.

Authors

Alice R. Burton, Laura J. Pallett, Laura E. McCoy, Kornelija Suveizdyte, Oliver E. Amin, Leo Swadling, Elena Alberts, Brian R. Davidson, Patrick T.F. Kennedy, Upkar S. Gill, Claudia Mauri, Paul A. Blair, Nadege Pelletier, Mala K. Maini

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Figure 2

atMBC are expanded in HBV infection and enriched in the HBsAg-specific compartment.

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atMBC are expanded in HBV infection and enriched in the HBsAg-specific c...
(A) Representative staining and cumulative data: HBsAg-specific MBC subsets (atMBC CD27–CD21–; actMBC CD27+CD21–, cMBC CD27+CD21+; gated on CD45+CD19+CD3–CD20+CD10–) in HBV-vaccinated HC (n = 27) and patients with CHB (n = 73). Each bar represents an individual. Individuals are ordered by increasing age (range: HBV-vaccinated HC = 21–89 years; CHB = 23–71 years). (B) Summary plots comparing the frequencies of HBsAg-specific MBC subsets between HBV-vaccinated HC (n = 27) and patients with CHB (n = 73). (C) Frequency of atMBC in the global B cell compartment in HBV-vaccinated HC (n = 61) and patients with CHB (n = 96). (D) Frequency of cells with an atMBC phenotype in the global compared with HBsAg-specific compartment (n = 49 patients with CHB). (E) Cross-sectional analysis of global atMBC in HBV-acute (n = 13) and HBV-resolved (n = 20) HBV infection (F) Longitudinal analysis of atMBC during acute-resolving infection. Frequencies plotted relative to viral load (dashed line; IU/ml), serum ALT (dotted line; IU/liter), and serological status (indicated by bars). Error bars indicate mean ± SEM. P values were determined by Mann-Whitney t test (B, C, and E) and Wilcoxon’s paired t test (D). *P < 0.05; ****P < 0.0001.