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TLR7 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.

Background: Currently, much effort is directed at further improving treatment for chronic hepatitis B patients by assessing the effect of immunomodulatory agents during therapy with nucleotide analogues (NUC). Although there are some reports on the effect of NUC therapy on peripheral natural killer (NK) cells, no studies investigated the long-term effects of NUC treatment on intrahepatic NK cells of chronic HBV patients. We aimed to prospectively investigate cell frequencies, phenotype, and activation status of intrahepatic NK cells of CHB patients on prolonged treatment with TDF. Methods: Fine needle aspiration biopsies were collected from 11 chronic HBV patients at baseline, and at 12, 24, and 48 weeks of treatment with a daily 245 mg dose of TOE Four patients underwent an additional aspiration biopsy after appoximately 6 years of treatment. Results: Longitudinal evaluation of these patients during tenofovir therapy showed that all patients achieved a viral load reduction with undetectable DNA load after 48 weeks of therapy. Repeated sampling of the liver during therapy showed that the frequency of distinct lymphocyte populations in the liver remained unchanged despite viral load reduction. During the course of therapy, no modulation of the expression levels and frequencies of CD69, HLA-DR, NKG2A and NKG2D on liver NK cells were detected. However, evaluation of intrahepatic NK cell activation after continuous TDF therapy for 6 years demonstrated a mild increase in 3 out of 4 patients. Conclusions: Our findings provide a unique insight in the intrahepatic NK cell compartment in chronic HBV patients during prolonged treatment. We observed that long-term NUC-induced viral suppression, accompanied by gradual decrease of HBsAg levels, had no or only a limited effect on the frequencies, phenotype, and activation status of intrahepatic NK cells. (C) 2016 Elsevier B.V. All rights reserved.

Background Chronic HBV infection can be divided into 4 distinct clinical phases: immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis. Using a systems biology approach, we recently identified innate immune response components, specifically NK cells as a distinctive factor of specific HBV clinical phases. To expand on this study and identify the underlying immunological mechanisms, we performed a comprehensive profiling of NK cells in chronic HBV infection. Methods Peripheral blood from untreated chronic HBV patients was used to analyze phenotypic markers, as well as cytokine production and cytoxicity of NK cells. Results The overall composition, phenotype, and cytolytic activity of the NK cells remained constant across all clinical phases, with the exception of a few specific markers (KIRs, NKp46). CD56bright NK cells of chronic HBV patients differed in their ability to produce IFN-γ between the clinical phases pre- and post-HBeAg seroconversion. Conclusion This depicts a shift in NK cell characteristics between the immune active, under heavy viral or immune pressure, and inactive carrier phases, that coincides with HBeAg seroconversion. Although these changes in NK cells do not appear to be completely responsible for differences in liver damage characteristic of specific clinical phases, they could provide a step toward understanding immune dysregulation in chronic HBV infection.

Globally, over 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV). These chronic infections cause liver inflammation, and may result in fibrosis/cirrhosis or hepatocellular carcinoma. Albeit that HBV and HCV differ in various aspects, clearance, persistence, and immunopathology of either infection depends on the interplay between the innate and adaptive responses in the liver. Kupffer cells, the liver-resident macrophages, are abundantly present in the sinusoids of the liver. These cells have been shown to be crucial players to maintain homeostasis, but also contribute to pathology. However, it is important to note that especially during pathology, Kupffer cells are difficult to distinguish from infiltrating monocytes/macrophages and other myeloid cells. In this review we discuss our current understanding of Kupffer cells, and assess their role in the regulation of anti-viral immunity and disease pathogenesis during HBV and HCV infection. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Serum levels of interferon-gamma inducible protein 10 (IP-10) are a marker for immune activity, and may predict response to peginterferon (PegIFN) therapy in chronic hepatitis B.IP-10 was measured at baseline and on-treatment week 12 in 210 HBeAg-positive patients treated with PegIFN for 52 weeks. Response to treatment was assessed at 6 months post-treatment and defined as HBeAg loss, combined response (HBeAg loss with HBV DNA10,000 c/ml) or HBsAg loss.Median baseline IP-10 levels were 158 pg/ml. Higher baseline IP-10 was associated with more HBV DNA, HBeAg and HBsAg decline from week 4 onwards, and IP-10 was higher in patients who achieved HBeAg loss (p=0.001) and combined response (p=0.052). A combination of high IP-10 (150 pg/ml) with absence of precore (PC) and core promoter (BCP) mutants strongly predicted combined response and HBsAg loss: 48% of patients with high IP-10 and no detectable mutants achieved a combined response (p0.001). A minimal non-significant decline from baseline was observed to week 12 (0.015 log pg/ml, p=0.52 compared to baseline), but decline was somewhat more pronounced in patients who achieved HBeAg loss (0.05 logpg/ml, versus an increase of 0.05 in patients without HBeAg loss, p=0.04).Higher pre-treatment IP-10 levels are associated with an increased probability of HBeAg loss after PegIFN therapy. A combination of high baseline IP-10 and absence of PC and BCP mutants identified patients with the highest probability of combined response and HBsAg loss. There appears little use for on-treatment quantification of IP-10 for prediction of response to PegIFN.

Item does not contain fulltext The combination of ribavirin and peginterferon is the current standard of anti-viral treatment for chronic HCV patients. However, little is known on the mode of action of ribavirin in the anti-viral treatment of HCV patients. To investigate the immunomodulatory mechanism of ribavirin, we studied peginterferon alone versus peginterferon and ribavirin in chronic HBV patients. The addition of ribavirin did not affect the number of myeloid dendritic cells (mDC) or plasmacytoid dendritic cells (pDC), nor did it enhance T-helper-1 cell activity or T-cell proliferation. In contrast, it increased upregulation of activation markers on mDC and pDC, which was sustained throughout treatment. However, the addition of ribavirin had no effect on IFNalpha production by pDC. Our findings demonstrate that, although ribavirin does not lead to a viral load decline, in vivo treatment with ribavirin affects the activation of pDC and mDC in chronic HBV patients.

The immune response in patients chronically infected with HCV plays a unique role during the infection because of its potential to contribute not only to viral clearance and, in some cases, protective immunity, but also to liver injury. A detailed understanding of the immunological mechanisms involved in persistence to HCV is essential to fully appreciate the complexity of the disease. In recent years, enormous progress has been made to characterize the dysfunctional natural killer cells and T cells during the chronic phase of infection. This information is important to further optimize treatment strategies based on the strengthening antiviral and immunomodulatory activities in patients chronically infected with HCV. (c) 2012 Elsevier Ltd. All rights reserved.

Background & Aims: Weak hepatitis C virus (HCV) specific immunity in peripheral blood has been shown to be partially controlled by regulatory T cells (Treg). However, little is known about Treg present in livers of HCV-infected patients, their association with clinical parameters, and immunopathology resulting in disease progression. Methods:The frequency and phenotype of CD4+FoxP3+ Treg, conventional CD4+ T cells, and the distribution of lymphocytes and leukocytes were studied by multi-color flowcytometry in liver and peripheral blood of 43 chronic HCV patients at different phases of liver disease. Comparisons between healthy blood and liver and correlations with disease parameters were made. Results: An extensive lymphocyte infiltration containing abundant numbers of CD4+FoxP3+ Treg was present in HCV-infected livers, while absent from healthy liver. Moreover, in all patients, intrahepatic CD4+FoxP3+ Treg showed a fully differentiated and highly activated phenotype on the basis of the surface markers CD45RO, CCR7, CTLA-4 and HLA-DR. These Treg were more numerous in those HCV-infected livers showing only limited fibrosis. However, HCV RNA loads or alanine transaminase levels did not correlate with CD4+FoxP3+ Treg frequencies. Conclusions: Our data demonstrate that large numbers of highly activated and differentiated CD4+FoxP3+ Treg localize to the infiltrated chronic HCV-infected liver and may result in limiting the extent of fibrosis. This suggests that CD4+FoxP3+ Treg play a pivotal role in limiting collateral damage by suppressing excessive HCV-induced immune activation. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The present study is part of a project that focuses on the relationship between environmental pollution and fish diseases. Field studies in various polluted coastal areas in Europe and the United States of America clearly indicate a relationship between pollution and the increase in prevalence of tumours and infectious diseases in fish. Research under controlled laboratory conditions is necessary to prove causal links between specific xenobiotics and disease prevalence. One of the chemicals of interest in the myriad of xenobiotics found in polluted waters and sediments is the organotin compound tributyltin (TBT), originating mainly from antifouling paints used on the hulls of ships. This report describes a study in which flounders (Platichthys flesus) were exposed to bis(tri-n-butyltin)oxide (TBTO) in the water under controlled laboratory conditions. The effects on several organs (gills, skin, eye, liver, mesonephros, ovary/testis, spleen, and gastrointestinal tract) were examined using histopathology, and morphometric analysis of the thymus was performed to assess the target organ(s) for TBTO in this fish species. Also the function of the non-specific and specific resistance was studied using ex vivo/in vitro immune function tests. Exposure of flounder to TBTO, in concentrations which were in the same order of magnitude as maximum TBT levels measured in the field (experiment: 17.3 μg TBT/l; field: 7.2 μg TBT/l), caused mortality after 7–12 days, resulted in gill lesions, and induced significant reduction of the non-specific resistance. A significant decrease of the relative thymus volume, but no marked effects on the specific immune system were noted after exposure to TBTO.

Hepatitis B core-related antigen (HBcrAg), a new serum marker, may be useful in monitoring chronic hepatitis B infection. HBcrAg was measured in 175 hepatitis B e antigen-positive patients treated with entecavir (ETV) with or without peginterferon (PEG-IFN) add-on therapy. Decline in HBcrAg was stronger in patients with vs. without combined response (ETV: -3.22 vs. -1.71 log U/mL, p