Burton, Alice Roselyn;
(2019)
Defective circulating and intrahepatic B cells in chronic HBV.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
B cells are increasingly recognised to play an important role in the ongoing control of chronic viral infections, yet their contribution to the persistence of HBV is poorly understood. The development of antibodies against HBV envelope protein (HBsAg) is considered the hallmark of resolution of acute infection; accordingly, seroconversion against HBsAg represents a key therapeutic goal for functional cure of chronic HBV (CHB). The production of inadequate anti-HBsAg (anti-HBs) antibodies to neutralise large quantities of circulating HBsAg in chronic infection suggests there may be defects in the B cell response upon HBV infection. To investigate constraints on their antiviral potential, global and antigen-specific B cells were characterised directly ex vivo from the blood and liver of patients with CHB. HBsAg-specific B cells persisted in the blood and liver in patients with CHB at similar frequencies to patients with acute-resolving infection and healthy HBV-vaccinated controls. However, differentiation of HBsAg-specific B cells from patients with CHB demonstrated decreased antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cell compartments had an accumulation of CD27-CD21low/- atypical memory B cells (atMBCs), characterised by high expression of inhibitory receptors, including PD-1. These atMBCs demonstrated altered signalling, homing, differentiation into antibody-producing cells, survival and antiviral cytokine production, that could be partially rescued by PD-1 blockade. PD-1hi atMBCs were further expanded in healthy and HBV-infected livers compared to the periphery, implicating the combination of this tolerogenic niche and HBV infection in driving PD-1hi atMBCs and impairing B cell immunity. Finally, the identification of endogenous antigen-specific B cells demonstrates previously unappreciated potential for these cells in natural control of HBV that may be enhanced through immunotherapeutic targeting. Work presented in this thesis has start to identify targets for reconstitution of their antiviral efficacy.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Defective circulating and intrahepatic B cells in chronic HBV |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10066980 |
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