Circulating and intrahepatic antiviral B cells are defective in hepatitis B

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 f...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-10, Vol.128 (10), p.4588-4603
Main Authors: Burton, Alice R, Pallett, Laura J, McCoy, Laura E, Suveizdyte, Kornelija, Amin, Oliver E, Swadling, Leo, Alberts, Elena, Davidson, Brian R, Kennedy, Patrick T F, Gill, Upkar S, Mauri, Claudia, Blair, Paul A, Pelletier, Nadege, Maini, Mala K
Format: Article
Language:English
Subjects:
Antibodies
Antigen presentation
Antiviral drugs
Biomedical research
CD27 antigen
Chronic infection
Cytotoxicity
Driving ability
Gastroenterology
Hepatitis
Hepatitis B
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
Immunoglobulins
Immunological memory
Infections
Inflammation
Liver
Lymphocytes
Lymphocytes B
Memory cells
PD-1 protein
Roles
T cell receptors
Transplants & implants
Viral infections
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Summary: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. HBsAgspecific 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 antibodyproducing 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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI121960.