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The Effect of Chronic Hepatitis B Virus Infection on BDCA3+ Dendritic Cell Frequency and Function.

ABSTRACT: Chronic hepatitis B virus (HBV) infection results from inadequate HBV-specific immunity. BDCA3+ dendritic cells (DCs) are professional antigen presenting cells considered to be important for antiviral responses because of specific characteristics, including high interferon-? production. BDCA3+ DCs may thus also have a role in the immune response against HBV, and immunotherapeutic strategies aiming to activate DCs, including BDCA3+ DCs, in patient livers may represent an interesting treatment option for chronic HBV. However, neither the effect of chronic hepatitis B (CHB) infection on the frequency and function of BDCA3+ DCs in liver and blood, nor the effect of the viral surface protein (HBsAg) that is abundantly present in blood of infected individuals are known. Here, we provide an overview of BDCA3+ DC frequency and functional capacity in CHB patients. We find that intrahepatic BDCA3+ DC numbers are increased in CHB patients. BDCA3+ DCs from patient blood are not more mature at steady state, but display an impaired capacity to mature and to produce interferon-? upon polyI:C stimulation. Furthermore, in vitro experiments exposing blood and intrahepatic BDCA3+ DCs to the viral envelope protein HBsAg demonstrate that HBsAg does not directly induce phenotypical maturation of BDCA3+ DCs, but may reduce IFN-? production via an indirect unknown mechanism. These results suggest that BDCA3+ DCs are available in the blood and on site in HBV infected livers, but measures may need to be taken to revive their function for DC-targeted therapy.

SUBMITTER: van der Aa E

PROVIDER: S-EPMC4987041 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Effect of Chronic Hepatitis B Virus Infection on BDCA3+ Dendritic Cell Frequency and Function.

van der Aa Evelyn E Buschow Sonja I SI Biesta Paula J PJ Janssen Harry L A HL Woltman Andrea M AM

PloS one 20160816 8

Chronic hepatitis B virus (HBV) infection results from inadequate HBV-specific immunity. BDCA3+ dendritic cells (DCs) are professional antigen presenting cells considered to be important for antiviral responses because of specific characteristics, including high interferon-λ production. BDCA3+ DCs may thus also have a role in the immune response against HBV, and immunotherapeutic strategies aiming to activate DCs, including BDCA3+ DCs, in patient livers may represent an interesting treatment opt ...[more]

PMID: 27529176

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Project description:Background and aims: Chronic hepatitis B virus (HBV) infection is a major health burden potentially evolving toward cirrhosis and hepatocellular carcinoma. HBV physiopathology is strongly related to the host immunity, yet the mechanisms of viral evasion from immune-surveillance are still misunderstood. The immune response elicited at early stages of viral infection is believed to be important for subsequent disease outcome. Dendritic cells (DCs) are crucial immune sentinels which orchestrate antiviral immunity, which offer opportunity to pathogens to subvert them to escape immunity. Despite the pivotal role of DCs in orientating antiviral responses and determining the outcome of infection, their precise involvement in HBV pathogenesis is not fully explored. Methods: One hundred thirty chronically HBV infected patients and 85 healthy donors were enrolled in the study for blood collection, together with 29 chronically HBV infected patients and 33 non-viral infected patients that were included for liver biopsy collection. In a pioneer way, we investigated the phenotypic and functional features of both circulating and intrahepatic BDCA1+ cDC2, BDCA2+ pDCs, and BDCA3+ cDC1 simultaneously in patients with chronic HBV infection by designing a unique multi-parametric flow cytometry approach. Results: We showed modulations of the frequencies and basal activation status of blood and liver DCs associated with impaired expressions of specific immune checkpoints and TLR molecules on circulating DC subsets. Furthermore, we highlighted an impaired maturation of circulating and hepatic pDCs and cDCs following stimulation with specific TLR agonists in chronic HBV patients, associated with drastic dysfunctions in the capacity of circulating DC subsets to produce IL-12p70, TNFα, IFNα, IFNλ1, and IFNλ2 while intrahepatic DCs remained fully functional. Most of these modulations correlated with HBsAg and HBV DNA levels. Conclusion: We highlight potent alterations in the distribution, phenotype and function of all DC subsets in blood together with modulations of intrahepatic DCs, revealing that HBV may hijack the immune system by subverting DCs. Our findings provide innovative insights into the immuno-pathogenesis of HBV and the mechanisms of virus escape from immune control. Such understanding is promising for developing new therapeutic strategies restoring an efficient immune control of the virus.

Project description:ObjectiveTo explore the correlation between postpartum hepatitis and changes of plasmacytoid dendritic cells' (pDC) function and frequency in hepatitis B e antigen (HBeAg)-positive pregnant women with chronic hepatitis B virus (HBV) infection.MethodsPregnant women with chronic HBV infection receiving antiviral treatment (treated group) or not receiving antiviral treatment (untreated group) were enrolled and demographic information was collected before delivery. Clinical biochemical, virological serology, pDC frequency and functional molecular expression were tested before delivery and at 6, 12, 24 weeks after delivery.Results90 eligible pregnant women were enrolled, 36 in the untreated group and 54 in the treated group. 36 patients developed postpartum hepatitis, including 17 (17/36, 47.2%) in the untreated group and 19 (19/54, 35.2%) in the treated group (χ2 = 1.304 p=0.253), and 22 cases of hepatitis occurred at 6 weeks postpartum, 12 at 12 weeks postpartum, and 2 at 24 weeks postpartum. The alanine transaminase (ALT) levels at any time postpartum were significantly higher than that of the antepartum, especially at 6 weeks and 12 weeks postpartum. However, the frequencies of pDCs, CD83+ pDCs and CD86+ pDCs antepartum had no significant difference from any time postpartum. The frequencies of CD83+ pDCs, CD86+ pDCs in the treated group antepartum were significantly higher than those in the untreated group [12.70 (9.46, 15.08) vs. 10.20 (7.96, 11.85), p=0.007; 22.05 (19.28, 33.03) vs. 18.05 (14.33, 22.95), p=0.011], and the same at 12 weeks postpartum [12.80 (10.50, 15.50) vs. 9.38 (7.73, 12.60), p=0.017; 22.50 (16.80, 31.20) vs. 16.50 (12.65, 20.80), p=0.001]. The frequency of CD86+ pDCs in the treated group was significantly higher than that in the untreated group at 24 weeks postpartum [22.10 (16.70, 30.00) vs. 17.10 (13.70, 20.05), p=0.006].ConclusionsPostpartum hepatitis in HBV infected women mainly occurs at 6-12 weeks postpartum. Antiviral treatment during pregnancy can significantly increase the frequencies of CD83+ pDCs and CD86+ pDCs in pregnant women with chronic HBV infection.

Project description:Background & aimsChronic hepatitis C virus infection activates an intrahepatic immune response, leading to increased expression of interferon (IFN)-stimulated genes and activation of natural killer (NK) cells-the most prevalent innate immune cell in the liver. We investigated whether the elimination of hepatitis C virus with direct-acting antiviral normalizes expression of IFN-stimulated genes and NK cell function.MethodsWe used multicolor flow cytometry to analyze NK cells from the liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with daclatasvir and asunaprevir and compared with samples from the blood of 13 healthy individuals (controls). Serum levels of chemokine C-X-C motif ligand (CXCL) 10 or CXCL11 were measured by enzyme-linked immunosorbent assay.ResultsBefore treatment, all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from controls, characterized by increased expression of HLA-DR, NKp46, NKG2A, CD85j, signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). NK cells from patients also had increased degranulation and decreased production of IFNγ and tumor necrosis factor α compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic and blood NK cells; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until week 24 (end of treatment).ConclusionsDirect-acting antiviral-mediated clearance of HCV is associated with loss of intrahepatic immune activation by IFNα, which is indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function.

Dataset Information

The Effect of Chronic Hepatitis B Virus Infection on BDCA3+ Dendritic Cell Frequency and Function.

Publications

The Effect of Chronic Hepatitis B Virus Infection on BDCA3+ Dendritic Cell Frequency and Function.

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