B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection.
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1010179 |
| _version_ | 1811326277767921664 |
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| author | Clinton O Ogega Nicole E Skinner Andrew I Flyak Kaitlyn E Clark Nathan L Board Pamela J Bjorkman James E Crowe Andrea L Cox Stuart C Ray Justin R Bailey |
| author_facet | Clinton O Ogega Nicole E Skinner Andrew I Flyak Kaitlyn E Clark Nathan L Board Pamela J Bjorkman James E Crowe Andrea L Cox Stuart C Ray Justin R Bailey |
| author_sort | Clinton O Ogega |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T14:47:12Z |
| format | Article |
| id | doaj.art-ac048e1651254026a9cdd417471e0c03 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-13T14:47:12Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-ac048e1651254026a9cdd417471e0c032022-12-22T02:42:43ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-01-01181e101017910.1371/journal.ppat.1010179B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection.Clinton O OgegaNicole E SkinnerAndrew I FlyakKaitlyn E ClarkNathan L BoardPamela J BjorkmanJames E CroweAndrea L CoxStuart C RayJustin R BaileyAntibodies 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.https://doi.org/10.1371/journal.ppat.1010179 |
| spellingShingle | Clinton O Ogega Nicole E Skinner Andrew I Flyak Kaitlyn E Clark Nathan L Board Pamela J Bjorkman James E Crowe Andrea L Cox Stuart C Ray Justin R Bailey B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. PLoS Pathogens |
| title | B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. |
| title_full | B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. |
| title_fullStr | B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. |
| title_full_unstemmed | B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. |
| title_short | B cell overexpression of FCRL5 and PD-1 is associated with low antibody titers in HCV infection. |
| title_sort | b cell overexpression of fcrl5 and pd 1 is associated with low antibody titers in hcv infection |
| url | https://doi.org/10.1371/journal.ppat.1010179 |
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