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 4

atMBC express higher levels of inhibitory receptors.

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atMBC express higher levels of inhibitory receptors. (A–C) Representativ...
(A–C) Representative examples and cumulative data: expression of (A) BTLA (MFI; n = 16) and CD22 (MFI; n = 26); (B) FcyRII1B (MFI; n = 30) and FcRL5 (%; n = 83); and (C) PD-1 (%; n = 55) on atMBC and cMBC in patients with CHB. (D) Dimension reduction analysis visualized using tSNE identifying discrete populations of atMBC based on the expression profile CD21–CD27– FcRL5+. PD-1 expression on B cells was concentrated within IgM–IgD– atMBC (purple cluster). tSNE analysis was performed on the expression data for the markers BAFF-R, IgD, CD21, CD80, CD10, CD11c, CD27, FcRL5, CD20, IgM, PD-1, CD38, and CD24 as measured by flow cytometry on CD19+ events concatenated from patients with CHB (n = 8) and HBV-vaccinated HC (n = 8). (E) Frequencies of PD-1+ atMBC stratified by viral load (IU/ml) (n = 10 with HBV DNA <2 × 103; n = 31 with HBV DNA ≥2 × 103) and compared with HC (HC; n = 37). (F–H) Representative examples and cumulative data: paired analysis of marker expression on HBsAg-specific B cells (black) compared with global B cells (gray) from within the same patient with CHB and comparison of HBsAg-specific B cells in patients with CHB and vaccinated HC (white). Expression levels of (F) FcRL5 (%; n = 60 patients with CHB; n = 29 HBV-vaccinated HC), (G) PD-1 (%; n = 66 patients with CHB; n = 23 HBV-vaccinated HC), and (H) T-bet (%; n = 17 patients with CHB; n = 11 HBV-vaccinated HC). Error bars indicate mean ± SEM. P values were determined by Wilcoxon’s paired t test (A–C; F–H), Kruskal-Wallis test (ANOVA) with Dunn’s post hoc test for pairwise multiple comparisons (E), and Mann-Whitney t test for unpaired data (F–H). *P < 0.05; **P < 0.005; ***P < 0.001; ****P < 0.0001.