Is hepatitis C virus infection of dendritic cells a mechanism facilitating viral persistence?

Zhang

The Journal of Immunology

et al. 2007

119

102

Although dysfunctional dendritic cells contribute to inadequate adaptive immunity in chronic hepatitis B (CHB), underlying molecular mechanisms remain largely undefined. In this study, we examined B7-H1 expression on circulating myeloid dendritic cells (mDCs) in 46 CHB patients, 10 autoimmune hepatitis patients, and 10 healthy subjects as control. We found that B7-H1 expression is significantly up-regulated on circulating mDCs of CHB and autoimmune hepatitis patients compared with healthy individuals. The B7-H1 up-regulation was significantly correlated with an elevation of serum alanine aminotransaminase levels and plasma viral load. In addition, in vitro, both IFN-α and IFN-γ could strongly stimulate mDCs to express B7-H1. More importantly, elevated B7-H1 expression is also closely associated with the suppression of T cell immune function. In vitro blockade of B7-H1 signaling could not only down-regulate IL-10 and up-regulate IL-12 production by mDCs, but also enhance mDC-mediated allostimulatory capacity and cytokine production of T cells. Blockade of B7-H1 signaling could improve hepatitis B c Ag-pulsed monocyte-derived DC-induced IFN-γ production by autologous hepatitis B virus-specific T cells. These new findings suggested that chronic inflammation may contribute to B7-H1 up-regulation on mDCs in CHB patients, which potentially cause defective hepatitis B virus-specific T cell function and viral persistence. Our findings further support the notion that the blockade of B7-H1 may represent a novel therapeutic approach for this disease.

mentioning

confidence: 99%

B7-H1 Up-Regulation on Myeloid Dendritic Cells Significantly Suppresses T Cell Immune Function in Patients with Chronic Hepatitis B

Zhang

The Journal of Immunology

et al. 2007

119

102

“…[6][7][8] Mechanisms contributing to this progressive functional defect remain unclear but could involve (1) lack of CD4 T cell help, 7,9 (2) defective antigen-presenting cell function, 10 (3) impairment of HCV-specific immunity by regulatory T cells, 11 (4) expression of inhibitory receptors, 12,13 or (5) T cell exhaustion caused by chronic antigenic stimulation. The overall weak T cell responses observed along with viral persistence could also result from "holes" in the HCV-specific T cell repertoire or a preexisting functional defect of HCV-specific T cells before infection.…”

mentioning

confidence: 99%

Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection

et al. 2008

E fficient control of viral infections in various animaland human models depends on a wide array of mechanisms affecting swiftness and strength of antiviral cellular and humoral immune responses. Diversity of such mechanisms is highlighted by analysis of immune responses elicited by hepatitis C virus (HCV) in humans. Control of acute HCV infection correlates with strong, sustained, and broad virus-specific cellular immunity mediated by both CD4 and CD8 T cells. By contrast, HCV persistence has been associated with transient T cell responses in infected donors. 1 Two nonmutually exclusive mechanisms could explain inefficient immune control of HCV in chronically infected patients. Mutations of several HCV epitopes, described both in chimpanzees and humans, can lead to decreased viral recognition by CD8 T cells. [2][3][4][5] Functional decline of HCV-reactive T cells resulting from progressive loss of interleukin-2 (IL-2)

“…There are several reports, indicating that HCV virus may damage functional properties of these cells. HCV was found to bind to DC and replicate there, although at very low level [22]. Sarobe et al [23] have shown that HCV structural proteins impair maturation of DC.…”

Section: Discussionmentioning

confidence: 99%

Significance of Alterations in PBMC Immunophenotype of Children with Chronic Viral Hepatitis C – the Role of Dendritic Cells

et al. 2006

There are differences in the clinical course of chronic viral hepatitis C between adults and children, but it is generally accepted that the disease has cell-mediated immune background. The aim of this study was to evaluate PBMC subsets in children with chronic hepatitis C before treatment in order to find some predictive factors, useful for patients management. Several PBMC subsets, in particular lymphoid and dendritic cell (DC) ones, were tested by flow cytometry in HCV þ paediatric patients (n ¼ 46) and in control children matched in terms of age and sex (n ¼ 20). Data were subjected to extensive statistics. It was found that cells with cytotoxic potential such as CD8 þ CD28 -T cells, NK and NKT cells as well as lineage -HLA-DR þ DC were increased in per cent values, while CD4 þ T cells and CD4:CD8 ratio were decreased in hepatitis C group. In HCV þ patients, CD4 þ T cells were inversely correlated with alanine aminotransferase (ALT) levels and with viraemia. DC subset of myeloid origin (CD11c þ ) assessed both in per cent values and as mean fluorescence intensity (MFI) of HLA-DR expression was shown to be downregulated in hepatitis patients, in spite of increased numbers. To conclude, PBMC subsets, and in particular DC, are affected by HCV chronic infection in children, reflected by the correlation with clinical parameters, such as ALT and viraemia.