Ordered array of dendritic cells and CD8+ lymphocytes in portal infiltrates in chronic hepatitis C

Gallè, M.B.; DeFranco, Raffaella; Kerjaschki, Dontscho; Romanelli, Roberto Giulio; Montalto, Paolo; Geñtilini, Paolo; Pinzani, Massimo; Romagnoli, Paolo

doi:10.1046/j.1365-2559.2001.01241.x

Cited by 25 publications

(21 citation statements)

References 35 publications

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“…In the present study, we identified increased mRNA levels of the PDC markers, BDCA2 and CD123, suggesting that PDCs can be recruited to the liver in patients with chronic HCV infection. Consistent with this notion, CD80 ϩ , CD83 ϩ , and CD86 ϩ cells with DC morphology were identified in livers of HCV-infected patients (34). The functional capacity of those PDCs in the liver remains to be evaluated.…”

Section: Discussionmentioning

confidence: 54%

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

Dolganiuc

Chang

Kodys

et al. 2006

The Journal of Immunology

206

203

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IFN-α production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-α-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-α 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-α 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-α and increased TNF-α and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-α and IL-10 induced apoptosis and inhibited IFN-α production in PDCs. Neutralization of TNF-α and/or IL-10 prevented HCV core-induced inhibition of IFN-α production. We identified CD14+ monocytes as the source of TNF-α and IL-10 in the HCV core-induced inhibition of PDC IFN-α production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-α 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-α production. These mechanisms are likely to contribute to HCV viral escape from immune responses.

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Section: Discussionmentioning

confidence: 54%

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

Dolganiuc

Chang

Kodys

et al. 2006

The Journal of Immunology

206

203

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“…One possible mechanism is the increased migration of pDCs to the liver. Indeed, pDCs were shown to localize to the liver during HCV infection (38)(39)(40), where they are able to sense HCV-infected hepatocytes and produce large amounts of type I IFN (41). Another possibility could be that type I IFN induces the death of pDCs, as was recently described by Swiecki et al (42).…”

Section: Discussionmentioning

confidence: 87%

Sustained Hyperresponsiveness of Dendritic Cells Is Associated with Spontaneous Resolution of Acute Hepatitis C

Pelletier

Bédard

Said

et al. 2013

J Virol

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Some studies have reported that dendritic cells (DCs) may be dysfunctional in a subset of patients with chronic hepatitis C virus (HCV) infection. However, the function of DCs during acute HCV infection and their role in determining infectious outcome remain elusive. Here, we examined the phenotype and function of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) during acute HCV infection. Three groups of injection drug users (IDUs) at high risk of HCV infection were studied: an uninfected group, a group with acute HCV infection with spontaneous resolution, and a group with acute infection with chronic evolution. We examined the frequency, maturation status, and cytokine production capacity of DCs in response to the Toll-like receptor 4 (TLR4) and TLR7/8 ligands lipopolysaccharide (LPS) and single-stranded RNA (ssRNA), respectively. Several observations could distinguish HCV-negative IDUs and acute HCV resolvers from patients with acute infection with chronic evolution. First, we observed a decrease in the frequency of mature CD86؉ , programmed death-1 receptor ligand-positive (PDL1 ؉ ), and PDL2 ؉ pDCs. This phenotype was associated with the increased sensitivity of pDCs from resolvers and HCV-negative IDUs versus the group with acute infection with chronic evolution to ssRNA stimulation in vitro. Second, LPS-stimulated mDCs from resolvers and HCV-negative IDUs produced higher levels of cytokines than mDCs from the group with acute infection with chronic evolution. Third, mDCs from all patients with acute HCV infection, irrespective of their outcomes, produced higher levels of cytokines during the early acute phase in response to ssRNA than mDCs from healthy controls. However, this hyperresponsiveness was sustained only in spontaneous resolvers. Altogether, our results suggest that the immature pDC phenotype and sustained pDC and mDC hyperresponsiveness are associated with spontaneous resolution of acute HCV infection.A minor fraction of individuals infected with the hepatitis C virus (HCV) eliminate the virus spontaneously, while the majority develop persistent infection, which may lead to chronic liver diseases (1). Spontaneous resolution of acute HCV infection is associated with the development of a robust and sustained HCV-specific CD4 and CD8 T cell response (2). In contrast, such responses are weak, inefficient, or transient in individuals who develop chronic infection. Several mechanisms underlying this immune failure have been previously described. First, escape mutations in epitopes targeted by virus-specific CD8 ϩ T cells can occur early during acute HCV infection, and this correlates with virus persistence (3-6). Second, failure of HCV-specific CD4 helper T cells to proliferate and produce cytokines was associated with viral recurrence and persistence. This loss of CD4 T cell help may compromise the function of virus-specific CD8 T cells and contribute to the development of suboptimal or exhausted CD8 ϩ T cells (7-13). Dendritic cells (DCs) are the most potent antigen-presenting cells in the body, and ...

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“…As monocytes and DCs are capable of uptake of apoptotic and necrotic cells, both DCs in the liver and circulating DC precursors can be affected by the viral proteins to result in reduced Ag presentation, as seen in the chronic HCV-infected patients. Indeed, DCs were found in hepatitis C-infected livers in close contact with lymphatic vessels, providing evidence for the importance of DCs in the liver in HCV infection (29,64).…”

Section: Discussionmentioning

confidence: 92%

“…In HCV-infected livers, increased numbers of DCs are found concentrated around newly formed lymphatic vessels (29). Based on the observation that HCV core and NS3 proteins activate monocytes, the precursors for myeloid DCs, we tested the hypothesis that HCV core and NS3 proteins mediate some of the myeloid DC defects found in patients with chronic hepatitis C infection.…”

Section: Hcv Core and Ns3 Proteins Inhibit Myeloid DC Allostimulatorymentioning

confidence: 99%

Hepatitis C Virus Core and Nonstructural Protein 3 Proteins Induce Pro- and Anti-inflammatory Cytokines and Inhibit Dendritic Cell Differentiation

Dolganiuc¹,

Kodys²,

Kopasz³

et al. 2003

The Journal of Immunology

230

215

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Antiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-α production in monocytes. Degradation of I-κBα suggested involvement of NF-κB activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-α and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients’ DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.

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Ordered array of dendritic cells and CD8+ lymphocytes in portal infiltrates in chronic hepatitis C

Abstract: This evidence strongly suggests a critical role of dendritic cells and newly formed lymphatics in the pathogenesis and organization of the immune infiltrate that characterizes HCV-related chronic active hepatitis.

Cited by 25 publications

References 35 publications

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

Sustained Hyperresponsiveness of Dendritic Cells Is Associated with Spontaneous Resolution of Acute Hepatitis C

Hepatitis C Virus Core and Nonstructural Protein 3 Proteins Induce Pro- and Anti-inflammatory Cytokines and Inhibit Dendritic Cell Differentiation

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