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dc.contributor.authorDolganiuc, Angela
dc.contributor.authorChang, Serena S.
dc.contributor.authorKodys, Karen
dc.contributor.authorMandrekar, Pranoti
dc.contributor.authorBakis, Gennadiy
dc.contributor.authorCormier, Maureen
dc.contributor.authorSzabo, Gyongyi
dc.date2022-08-11T08:08:57.000
dc.date.accessioned2022-08-23T16:13:34Z
dc.date.available2022-08-23T16:13:34Z
dc.date.issued2006-11-04
dc.date.submitted2008-09-04
dc.identifier.citation<p>J Immunol. 2006 Nov 15;177(10):6758-68.</p>
dc.identifier.issn0022-1767 (Print)
dc.identifier.doi10.4049/jimmunol.177.10.6758
dc.identifier.pmid17082589
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33651
dc.description.abstractIFN-alpha production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-alpha-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-alpha production was tested in PBMCs or isolated PDCs after TLR9 stimulation. Treatment-naive patients with chronic HCV infection had reduced frequency of circulating PDCs due to increased apoptosis and showed diminished IFN-alpha production after stimulation with TLR9 ligands. These PDC defects correlated with the presence of HCV and were in contrast with normal PDC functions of sustained responders. HCV core protein, which was detectable in the plasma of infected patients, reduced TLR9-triggered IFN-alpha and increased TNF-alpha and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-alpha and IL-10 induced apoptosis and inhibited IFN-alpha production in PDCs. Neutralization of TNF-alpha and/or IL-10 prevented HCV core-induced inhibition of IFN-alpha production. We identified CD14+ monocytes as the source of TNF-alpha and IL-10 in the HCV core-induced inhibition of PDC IFN-alpha production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-alpha production. In conclusion, our results suggest that HCV interferes with antiviral immunity through TLR2-mediated monocyte activation triggered by the HCV core protein to induce cytokines that in turn lead to PDC apoptosis and inhibit IFN-alpha production. These mechanisms are likely to contribute to HCV viral escape from immune responses.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17082589&dopt=Abstract">Link to article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.4049/jimmunol.177.10.6758
dc.subjectAdult; Apoptosis; Cell Death; Cells, Cultured; Cohort Studies; Dendritic Cells; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Leukocytes, Mononuclear; Leukopenia; Male; Middle Aged; Monocytes; Viral Core Proteins
dc.subjectImmunology and Infectious Disease
dc.titleHepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection
dc.typeJournal Article
dc.source.journaltitleJournal of immunology (Baltimore, Md. : 1950)
dc.source.volume177
dc.source.issue10
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/318
dc.identifier.contextkey619030
html.description.abstract<p>IFN-alpha production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-alpha-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-alpha production was tested in PBMCs or isolated PDCs after TLR9 stimulation. Treatment-naive patients with chronic HCV infection had reduced frequency of circulating PDCs due to increased apoptosis and showed diminished IFN-alpha production after stimulation with TLR9 ligands. These PDC defects correlated with the presence of HCV and were in contrast with normal PDC functions of sustained responders. HCV core protein, which was detectable in the plasma of infected patients, reduced TLR9-triggered IFN-alpha and increased TNF-alpha and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-alpha and IL-10 induced apoptosis and inhibited IFN-alpha production in PDCs. Neutralization of TNF-alpha and/or IL-10 prevented HCV core-induced inhibition of IFN-alpha production. We identified CD14+ monocytes as the source of TNF-alpha and IL-10 in the HCV core-induced inhibition of PDC IFN-alpha production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-alpha production. In conclusion, our results suggest that HCV interferes with antiviral immunity through TLR2-mediated monocyte activation triggered by the HCV core protein to induce cytokines that in turn lead to PDC apoptosis and inhibit IFN-alpha production. These mechanisms are likely to contribute to HCV viral escape from immune responses.</p>
dc.identifier.submissionpathgsbs_sp/318
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages6758-68
dc.contributor.studentSerena S. Chang


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