Decreased interferon-<i>α</i>production and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C

Murakami, Hidehiro; Akbar, Sk. Md. Fazle; Matsui, Hidetaka; Horiike, Norio; Onji, Morikazu

doi:10.1111/j.1365-2249.2004.02550.x

Cited by 57 publications

(65 citation statements)

References 29 publications

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“…Reduced absolute numbers of the circulating PDCs were reported previously in patients with chronic HCV compared with controls (23)(24)(25). A HCV escape mechanism from IFN-␣-mediated antiviral effects would be most important in the liver, where HCV replicates and most of the virus and the virus-derived proteins are produced.…”

Section: Discussionmentioning

confidence: 89%

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: 89%

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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“…It is notable that in HIV infection, there is a reduction in the number of plasmacytoid DCs (which produce high levels of IFN-␣/␤) in the peripheral blood (71). Although in HCV infection, pDC numbers are not dramatically reduced, their IFN-␣ production capacity may be impaired (6,62). A recent study also suggested that there may be abnormalities in the ability of DCs from HCV ϩ patients to produce IL-15 in response to IFN-␣ stimulation (43).…”

Section: Cd28mentioning

confidence: 99%

Shared Alterations in NK Cell Frequency, Phenotype, and Function in Chronic Human Immunodeficiency Virus and Hepatitis C Virus Infections

Meier

Owen

Taylor

et al. 2005

J Virol

165

145

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Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause clinically important persistentinfections. The effects of virus persistence on innate immunity, including NK cell responses, and the underlying mechanisms are not fully understood. We examined the frequency, phenotype, and function of peripheral blood CD3 ؊ CD56 ؉ NK subsets in HIV ؉ and HCV ؉ patients and identified significantly reduced numbers of total NK cells and a striking shift in NK subsets, with a marked decrease in the CD56 dim cell fraction compared to CD56 bright cells, in both infections. This shift influenced the phenotype and functional capacity (gamma interferon production, killing) of the total NK pool. In addition, abnormalities in the functional capacity of the CD56 dim NK subset were observed in HIV ؉ patients. The shared NK alterations were found to be associated with a significant reduction in serum levels of the innate cytokine interleukin 15 (IL-15). In vitro stimulation with IL-15 rescued NK cells of HIV ؉ and HCV ؉ patients from apoptosis and enhanced proliferation and functional activity. We hypothesize that the reduced levels of IL-15 present in the serum during HIV and HCV infections might impact NK cell homeostasis, contributing to the common alterations of the NK pool observed in these unrelated infections.

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“…98,102,103 More importantly, while the amounts of IFN-␣ produced in vivo are insufficient to modulate the antigen-processing and antigen-presenting functions, they are certainly sufficient for transforming the PDCs into potent activators of adaptive immunity during chronic HCV infection. As reported by Murakami et al, 102 PDCs from patients with HCV induced significantly lower numbers of IFN-␥-producing effector T lymphocytes compared with that of controls. Furthermore, PDCs of patients primed more CD4 T cells producing IL-10 than those from normal controls.…”

Section: Dendritic Cells In Hcv Infectionmentioning

confidence: 99%

Altered innate immunity in chronic hepatitis C infection: Cause or effect?

2007

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H epatitis C virus (HCV) is a uniquely successful hepatitis virus in its ability to establish chronic infection in more than two-thirds of those who contract it. The inability of the innate and adaptive immune responses to control HCV invasion and replication contribute to development and persistence of chronic infection. Multiple components have been identified in this process, including pathways by which HCV subverts innate immune recognition and activation, delayed organization of an effective adaptive immune response, the tolerogenic liver environment, and the persistently high levels of viral antigens. We summarize recent findings on the interaction between HCV infection and innate immune responses. Hepatitis C Virus, Immune Responses and Hepatocytes-Brief OverviewA critical role for innate and adaptive immunity has been identified in HCV persistence and liver injury. During acute infection, type I interferon (IFN) is induced in the liver; however, HCV viral load does not decrease, suggesting that HCV interferes with antiviral mechanisms. Innate immune cells, including natural killer cells and dendritic cells shape innate immunity and determine adaptive immune activation. Vigorous, multi-epitopespecific, T helper 1-type and sustained CD4ϩ and CD8ϩ T cell responses were found in resolved acute HCV infections. [1][2][3][4] In contrast, in cases that progress to chronic infection, CD4ϩ T cell responses are weak, short-lived, and targeted to a narrow range of epitopes. 1

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Decreased interferon-αproduction and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C

Cited by 57 publications

References 29 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

Shared Alterations in NK Cell Frequency, Phenotype, and Function in Chronic Human Immunodeficiency Virus and Hepatitis C Virus Infections

Altered innate immunity in chronic hepatitis C infection: Cause or effect?

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