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PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection
Loghman Salimzadeh, … , Patrick T.F. Kennedy, Antonio Bertoletti
Loghman Salimzadeh, … , Patrick T.F. Kennedy, Antonio Bertoletti
Published August 7, 2018
Citation Information: J Clin Invest. 2018;128(10):4573-4587. https://doi.org/10.1172/JCI121957.
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Research Article Hepatology Infectious disease

PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection

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Abstract

Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as “baits” for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21lo) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti–PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell–maturing cytokines and PD-1 blockade.

Authors

Loghman Salimzadeh, Nina Le Bert, Charles-A. Dutertre, Upkar S. Gill, Evan W. Newell, Christian Frey, Magdeleine Hung, Nikolai Novikov, Simon Fletcher, Patrick T.F. Kennedy, Antonio Bertoletti

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Figure 3

Longitudinal profile of B cell responses in acute HBV patients.

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Longitudinal profile of B cell responses in acute HBV patients.
(A) Freq...
(A) Frequency of global plasmablasts (CD19+CD10–CD21–CD27++CD38++) out of total B cells (CD19+) were analyzed at the indicated different time points in 6 patients with acute HBV (left) and in 5 patients with acute dengue infection (right). Time points are indicated as days after onset of clinical symptoms. Virological features of acute HBV and dengue are indicated at the top of the figures. (B) Longitudinal frequency of HBsAg-specific B cells in the 6 acute hepatitis B patients compared with the frequency obtained in 21 subjects with resolved HBV infection (anti-HBc+, anti-HBs+; open circles). HBsAg-specific B cells were calculated as the frequency of memory double-positive HBsAg-D550+D650+ B cells out of total CD19+ B cells. Each symbol represents a single patient.
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