Altered Functions of Plasmacytoid Dendritic Cells and Reduced Cytolytic Activity of Natural Killer Cells in Patients With Chronic HBV Infection

Martinet, J.; Dufeu‐Duchesne, Tania; Costa, Juliana Bruder; Larrat, Sylvie; Marlu, Alice; Leroy, Vincent; Plumas, Joël; Aspord, Caroline

doi:10.1053/j.gastro.2012.08.046

Cited by 110 publications

(107 citation statements)

References 46 publications

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“…The ability of pDCs to produce IFN-a is impaired specifically in response to TLR9 but not to TLR7 agonists [41]. HBV escapes antiviral immunity by inhibiting TLR-9-mediated activation of pDCs, with consequent disruption of the interactions between pDCs and NK cells, resulting in reduced activity of NK cells in patients with chronic HBV infection [42]. Regarding the mechanisms, HBsAg is the causal factor for such disruption of the pDCs, partly by upregulating suppressor molecule SOCS-1 [41].…”

Section: Nk Cells and Dcs In Chronic Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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Section: Nk Cells and Dcs In Chronic Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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“…One study by Martinet et al 22 showed that the expression of CD40 and CD86 was increased in pDCs from HBV patients; however, the reduced expression of the OX40 ligand in highly viremic patients was also observed. 22 In terms of their ability to stimulate T-cell ,, lower than healthy;…”

Section: Overviewmentioning

confidence: 99%

“…A majority of studies showed that TLR-9 mediated IFN-a production by pDCs is reduced in chronic HBV patients compared with healthy pDCs. 15,[21][22][23]25 The mechanism of reduced IFN-a production remains to be determined. The downregulation of TLR-9 26 and interference with the mTOR pathway 21 have been suggested as potential mechanisms, but these studies were performed on healthy donor pDCs exposed to HBV in vitro.…”

Section: Dendritic Cells In Chronic Hbv Aj Gehring and Ja D'angelomentioning

confidence: 99%

“…It seems unlikely that this effect would be directly modulated by the virus or viral antigens because four studies found no correlation between the viral load in patients and reduced IFN-a production by pDCs. 15,16,21,22 Two studies have stated that IFN-a production by pDCs negatively correlated with ALT. 15,21 Therefore, regulatory mechanisms to control inflammation during chronic viral infection may alter the ability of pDCs to produce IFN-a.…”

Section: Dendritic Cells In Chronic Hbv Aj Gehring and Ja D'angelomentioning

confidence: 99%

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Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

Gehring

D’Angelo

2014

Cell Mol Immunol

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Therapeutic vaccines to boost endogenous T-cell immunity rely on the stimulatory capacity of dendritic cells (DCs). The functionality of DCs in chronic hepatitis B virus (HBV) infection has been a long-standing debate. Therefore, we have attempted to summarize multiple studies investigating DC function in chronic HBV patients to determine whether common observations can be drawn. We found that the frequency and function of ex vivo-tested myeloid and plasmacytoid DCs were largely intact in patients with HBV infection and similar to those of healthy donor DCs. The main exception was reduced IFN-a production by plasmacytoid DC from chronic HBV patients. This reduced IFN-a production correlated with liver inflammation in multiple studies but not with viral load, suggesting that viral antigens have little effect on DC function. The majority of the confusion about DC function arises from studies reporting the reduced function of healthy donor DCs exposed to various sources of HBV in vitro. These direct effects of viral antigens are in contrast to data from HBV-infected patients. The variations in the assays used and areas that require further investigation are also covered

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“…This difference is believed to derive from expression differences of X-chromosomal genes downstream of TLR7, combined with hormonal effects (Seillet et al, 2012(Seillet et al, , 2013Griesbeck et al, 2015). In addition, chronic HBV (CHB) infection itself can also impair pDC function; HBV impairs IFNα secretion and other pDC functions in response to TLR9 ligation (Woltman et al, 2011;Martinet et al, 2012aMartinet et al, , 2012b. Whether rs179008, sex or CHB affect pDC phenotypic maturation in response to TLR7 ligands is not known.…”

Section: Introductionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

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Altered Functions of Plasmacytoid Dendritic Cells and Reduced Cytolytic Activity of Natural Killer Cells in Patients With Chronic HBV Infection

Cited by 110 publications

References 46 publications

Host–virus interactions in hepatitis B and hepatitis C infection

Host–virus interactions in hepatitis B and hepatitis C infection

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

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