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 3

atMBC in CHB have altered T-bet expression and homing profiles.

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atMBC in CHB have altered T-bet expression and homing profiles. Represen...
Representative examples and cumulative data: expression of (A) T-bet on global atMBC and cMBC (%; n = 30) and (B) percentage of MBC subsets within T-bethi, T-betint, or T-betlo fractions (pregated on CD20+CD19+CD10–; n = 15). Gates were drawn on total CD45+ lymphocytes, as shown. (C) Expression of CD11c (%; n = 24) on global atMBC and cMBC in patients with CHB. (D) Expression of CD11c (%; n = 10) and CXCR3 (mean fluorescence intensity [MFI]; n = 10) on T-bethi (black), T-betint (gray), or T-betlo (white) atMBC. (E and F) Expression of (E) CXCR5 (MFI; n = 33) and (F) CD80 (MFI; n = 30) on global atMBC and cMBC in patients with CHB. (G) Frequency of class-switched cells (IgM–IgD–) as a percentage of naive, cMBC, and atMBC (n = 39 patients with CHB). Error bars indicate mean ± SEM. P values were determined by Wilcoxon’s paired t test (A, C, E, and F) and Kruskal-Wallis test (ANOVA) with Dunn’s post hoc test for pairwise multiple comparisons (D and G). *P < 0.05; **P < 0.005; ****P < 0.0001.