Patients with chronic hepatitis B infection display deficiency of plasmacytoid dendritic cells with reduced expression of TLR9

Xie, Qing; Shen, Huai-Cheng; Jia, Ni-Na; Wang, Hui; Lin, Lingnan; An, Bao-Yan; Gui, Honglian; Guo, Simin; Cai, Wei; Yu, Hong; Guo, Qing; Bao, Shisan

doi:10.1016/j.micinf.2009.02.008

Cited by 78 publications

(82 citation statements)

References 28 publications

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“…Zhou et al 21 also reported that expression levels of TLR9 were significantly decreased in the CHB patients. In parallel with our results, Xie and colleagues 22 also showed that expression levels of TLR9 mRNA and protein levels were decreased in plasmacytoid dendritic cells of CHB patients when compared with healthy controls. All of these studies measured only TLR9 mRNA levels, whereas our study evaluated some of the downstream signaling molecules and revealed that these molecules also were decreased.…”

Section: Expression Levels Of Target Genessupporting

confidence: 91%

Decreased Expressions of Toll-Like Receptor 9 and Its Signaling Molecules in Chronic Hepatitis B Virus–Infected Patients

Sajadi

Mirzaei

Hassanshahi

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Toll-like receptors (TLRs) play crucial roles in immune responses, especially innate immunity, against viral infections. Toll-like receptor 9 recognizes intracellular viral double-strand DNA, which leads to the activation of nuclear factor B (NF-jB) through the myeloid differentiation primary response 88 (MYD88) pathway. Defects in the expression of TLR9 and its signaling molecules may cause attenuated immune responses against hepatitis B virus.Objective.-To determine expression levels of TLR9 messenger RNA along with MYD88, interleukin 1 receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), and NF-jB in the peripheral blood mononuclear cells obtained from chronic hepatitis B virus (CHB)-infected patients.Design.-In this study, 60 CHB patients and 60 healthy controls were recruited and the expression of TLR9 and its downstream signaling molecules was examined by realtime polymerase chain reaction techniques using b-actin as a housekeeping gene.Results.-Our results showed that expression of TLR9, MYD88, IRAK1, TRAF6, and NF-jB in peripheral blood mononuclear cells of CHB patients was significantly decreased in comparison with healthy controls.Conclusions.-According to our results, it appears that CHB patients are unable to appropriately express genes in the TLR9 pathway, which may impede immune responses against hepatitis B virus infection. These results suggest a mechanism that may partially explain the fact that immune responses are disrupted in CHB patients.

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Section: Expression Levels Of Target Genessupporting

confidence: 91%

Decreased Expressions of Toll-Like Receptor 9 and Its Signaling Molecules in Chronic Hepatitis B Virus–Infected Patients

Sajadi

Mirzaei

Hassanshahi

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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“…The persistent presence of high quantities of virions and viral antigens in the circulation of patients with chronic hepatitis B has been associated with the immunological alterations present in these patients. Specifically, that persistent exposure to HBV and HBsAg alters the frequency and function of myeloid, plasmacytoid, and moDCs (11,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). The previous reports regarding the HBsAg inhibitory effects were largely related to TLR-mediated cytokine production and could affect innate immunity pathways.…”

Section: Discussionmentioning

confidence: 99%

Mobilizing monocytes to cross-present circulating viral antigen in chronic infection

Gehring

Haniffa²,

Kennedy³

et al. 2013

J. Clin. Invest.

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Selection of antigens for therapeutic vaccination against chronic viral infections is complicated by pathogen genetic variations. We tested whether antigens present during persistent viral infections could provide a personalized antigenic reservoir for therapeutic T cell expansion in humans. We focused our study on the HBV surface antigen (HBsAg), which is present in microgram quantities in the serum of chronic HBV patients. We demonstrated by quantitative fluorescent microscopy that, out of 6 professional APC populations in the circulation, only CD14 monocytes (MNs) retained an HBsAg depot. Using TCR-redirected CD8 + T cells specific for MHC-I-restricted HBV epitopes, we showed that, despite being constantly exposed to antigen, ex vivoisolated APCs did not constitutively activate HBV-specific CD8 + T cells. However, differentiation of HBsAg + CD14 MNs from chronic patients to MN-derived DCs (moDCs) induced cross-presentation of the intracellular reservoir of viral antigen. We exploited this mechanism to cross-present circulating viral antigen and showed that moDCs from chronically infected patients stimulated expansion of autologous HBV-specific T cells. Thus, these data demonstrate that circulating viral antigen produced during chronic infection can serve as a personalized antigenic reservoir to activate virus-specific T cells. IntroductionTherapeutic vaccination for chronic infections, be it recombinant antigens, peptides, viral vectors, DNA, or DCs, are hindered by the need to select appropriate antigens. It is a major complicating factor due to the evolutionary diversity that pathogens have developed in response to selective forces exerted by individual (immune response) or environmental (drugs, vectors) factors. Moreover, peptides covering conserved regions for vaccination are HLA restricted and can only be applied to selected patients with the appropriate HLA. As a result, recombinant antigens or DNA vectors coding pathogen proteins may misdirect the intended immune response due to differences between the infectious pathogen and the antigen sequence utilized for vaccination.A hallmark of many chronic infections is the constant production of pathogen proteins. This is particularly evident in HBV infection, where viral titers can reach 10 9 -10 10 virions/ml in the serum. The HBV surface antigen (HBsAg) is produced in excess of whole virions and reaches concentrations well into the μg/ml range (1). While persistently present viral antigen is generally considered a negative factor (2), the abundance of endogenously produced viral antigen could be internalized by different cell types. Proper activation of cells internalizing antigen in the circulation of chronic patients could provide a target for therapeutic vaccination and stimulate T cells with antigen customized to the patient's viral genome.HBV does not infect or productively replicate in human PBMCs (3), and systematic analysis of cells capable of internalizing circu-

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“…It has been reported that in CHB patients, HBV-specific immune responses are either absent or low, with deficiency of innate and adaptive immune cells and reduced expression of TLRs. 25 HBV has also been shown to suppress TLR-mediated innate immune responses in parenchymal and nonparenchymal liver cells. 5 In this study, we observed that the expressions of innate immune receptor RIG-I, type I IFNs, and IFNs-inducible antiviral genes were all lower in HBVtransfected HepG2.2.15 cells than those in virus-free HepG2 cells (Supporting Fig.…”

Section: Discussionmentioning

confidence: 99%

Reversal of hepatitis B virus-induced immune tolerance by an immunostimulatory 3p-HBx-siRNAs in a retinoic acid inducible gene I–dependent manner

Han

Zhang

et al. 2011

Hepatology

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It is extensively accepted that hepatitis B virus (HBV) escapes from innate immunity by inhibiting type I interferon (IFN) production, but efficient intervention to reverse the immune tolerance is still not achieved. Here, we report that 5 0 -end triphosphate hepatitis B virus X gene (HBx)-RNAs (3p-HBx-short interfering [si]RNAs) exerted significantly stronger inhibitory effects on HBV replication than regular HBx-siRNAs in stably HBV-expressing hepatoplastoma HepG2.2.15 cells through extremely higher expression of type I IFNs, IFN-induced genes and proinflammatory cytokines, and retinoic acid inducible gene I (RIG-I) activation. Also, 3p-HBx-siRNA were more efficient to stimulate type I IFN response than HBx sequenceunrelated 3p-scramble-siRNA in HepG2.2.15 cells, indicating that a stronger immune-stimulating effect may partly result from the reversal of immune tolerance through decreasing HBV load. In RIG-I-overexpressed HepG2.2.15 cells, 3p-HBx-siRNAs exerted stronger inhibitory effects on HBV replication with greater production of type I IFNs; on the contrary, in RIG-Isilenced HepG2.2.15 cells or after blockade of IFN receptor by monoclocnal antibody, inhibitory effect of 3p-HBx-siRNAs on HBV replication was largely attenuated, indicating that immunostimulatory function of 3p-HBx-siRNAs was RIG-I and type I IFN dependent. Moreover, in HBV-carrier mice, 3p-HBx-siRNA more strongly inhibited HBV replication and promoted IFN production than HBx-siRNA in primary HBV 1 hepatocytes and, therefore, significantly decreased serum hepatitis B surface antigen and increased serum IFN-b. Conclusion: 3p-HBx-siRNAs may not only directly inhibit HBV replication, but also stimulate innate immunity against HBV, which are both beneficial for the inversion of HBV-induced immune tolerance.

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Patients with chronic hepatitis B infection display deficiency of plasmacytoid dendritic cells with reduced expression of TLR9

Cited by 78 publications

References 28 publications

Decreased Expressions of Toll-Like Receptor 9 and Its Signaling Molecules in Chronic Hepatitis B Virus–Infected Patients

Decreased Expressions of Toll-Like Receptor 9 and Its Signaling Molecules in Chronic Hepatitis B Virus–Infected Patients

Mobilizing monocytes to cross-present circulating viral antigen in chronic infection

Reversal of hepatitis B virus-induced immune tolerance by an immunostimulatory 3p-HBx-siRNAs in a retinoic acid inducible gene I–dependent manner

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