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B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection

Ogega, Clinton O. and Skinner, Nicole E. and Flyak, Andrew I. and Clark, Kaitlyn E. and Board, Nathan L. and Bjorkman, Pamela J. and Crowe, James E., Jr. and Cox, Andrea L. and Ray, Stuart C. and Bailey, Justin R. (2022) B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. PLOS Pathogens, 18 (1). Art. No. e1010179. ISSN 1553-7374. PMCID PMC8769295. doi:10.1371/journal.ppat.1010179. https://resolver.caltech.edu/CaltechAUTHORS:20220111-570009300

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Abstract

Antibodies targeting the hepatitis C virus (HCV) envelope glycoprotein E2 are associated with delayed disease progression, and these antibodies can also facilitate spontaneous clearance of infection in some individuals. However, many infected people demonstrate low titer and delayed anti-E2 antibody responses. Since a goal of HCV vaccine development is induction of high titers of anti-E2 antibodies, it is important to define the mechanisms underlying these suboptimal antibody responses. By staining lymphocytes with a cocktail of soluble E2 (sE2) glycoproteins, we detected HCV E2-specific (sE2+) B cells directly ex vivo at multiple acute infection timepoints in 29 HCV-infected subjects with a wide range of anti-E2 IgG titers, including 17 persistently infected subjects and 12 subjects with spontaneous clearance of infection. We performed multi-dimensional flow cytometric analysis of sE2+ and E2-nonspecific (sE2-) class-switched B cells (csBC). In sE2+ csBC from both persistence and clearance subjects, frequencies of resting memory B cells (rMBC) were reduced, frequencies of activated MBC (actMBC) and tissue-like MBC (tlMBC) were increased, and expression of FCRL5, an IgG receptor, was significantly upregulated. Across all subjects, plasma anti-E2 IgG levels were positively correlated with frequencies of sE2+ rMBC and sE2+ actMBC, while anti-E2 IgG levels were negatively correlated with levels of FCRL5 expression on sE2+ rMBC and PD-1 expression on sE2+ actMBC. Upregulation of FCRL5 on sE2+ rMBC and upregulation of PD-1 on sE2+ actMBC may limit anti-E2 antibody production in vivo. Strategies that limit upregulation of these molecules could potentially generate higher titers of protective antibodies against HCV or other pathogens.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1371/journal.ppat.1010179DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8769295/PubMed CentralArticle
ORCID:
AuthorORCID
Ogega, Clinton O.0000-0001-9700-1015
Skinner, Nicole E.0000-0003-4807-022X
Flyak, Andrew I.0000-0002-8722-479X
Clark, Kaitlyn E.0000-0003-2375-8992
Board, Nathan L.0000-0002-5208-9970
Bjorkman, Pamela J.0000-0002-2277-3990
Crowe, James E., Jr.0000-0002-0049-1079
Cox, Andrea L.0000-0002-9331-2462
Ray, Stuart C.0000-0002-1051-7260
Bailey, Justin R.0000-0001-5704-3130
Additional Information:© 2022 Ogega et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: October 6, 2021; Accepted: December 7, 2021; Published: January 6, 2022. We thank all the participants in the BBAASH cohort and members of the Johns Hopkins Viral Hepatitis Center for thoughtful discussion. We thank the Bloomberg Flow Cytometry and Immunology Core, Tricia Nilles, MS, and Hao Zhang. M.D. for equipment and technical assistance. Funding was obtained from the National Institutes of Health (www.NIH.gov) grants R01AI127469 and R21AI151353 (to J.R.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: I have read the journal’s following competing interests. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received unrelated sponsored research agreements from Takeda Vaccines, IDBiologics and AstraZeneca. All other authors declare that they have no conflicts of interest. Author Contributions: Conceptualization: Clinton O. Ogega, Nicole E. Skinner, James E. Crowe, Jr., Andrea L. Cox, Stuart C. Ray, Justin R. Bailey. Data curation: Clinton O. Ogega, Justin R. Bailey. Formal analysis: Clinton O. Ogega, Nicole E. Skinner, Nathan L. Board, Stuart C. Ray, Justin R. Bailey. Funding acquisition: Justin R. Bailey. Investigation: Clinton O. Ogega, Nicole E. Skinner, Kaitlyn E. Clark, Nathan L. Board, James E. Crowe, Jr., Justin R. Bailey. Methodology: Clinton O. Ogega, Nicole E. Skinner, Andrew I. Flyak, Pamela J. Bjorkman, James E. Crowe, Jr., Andrea L. Cox, Stuart C. Ray, Justin R. Bailey. Project administration: Justin R. Bailey. Resources: Andrew I. Flyak, Pamela J. Bjorkman, Justin R. Bailey. Supervision: Justin R. Bailey. Validation: Justin R. Bailey. Writing – original draft: Clinton O. Ogega, Justin R. Bailey. Writing – review & editing: Clinton O. Ogega, Nicole E. Skinner, Andrew I. Flyak, Kaitlyn E. Clark, Nathan L. Board, Pamela J. Bjorkman, Andrea L. Cox, Stuart C. Ray, Justin R. Bailey.
Funders:
Funding AgencyGrant Number
NIHR01AI127469
NIHR21AI151353
Issue or Number:1
PubMed Central ID:PMC8769295
DOI:10.1371/journal.ppat.1010179
Record Number:CaltechAUTHORS:20220111-570009300
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220111-570009300
Official Citation:Ogega CO, Skinner NE, Flyak AI, Clark KE, Board NL, Bjorkman PJ, et al. (2022) B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. PLoS Pathog 18(1): e1010179. https://doi.org/10.1371/journal.ppat.1010179
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112831
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Jan 2022 22:26
Last Modified:25 Jan 2022 18:05

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