Role Of Hepatitis Research Articles

Gamma Delta T-lymphocytes in Hepatitis C and Chronic Liver Disease.

Discovered 30 years ago, gamma delta (γδ) T-lymphocytes remain an intriguing and enigmatic T-cell subset. Although in humans they comprise a small fraction of the total circulating T-lymphocyte pool, they represent an important T-cell subset in tissues such as the liver, with roles bridging the innate and adaptive immune systems. The associations of γδ T-lymphocytes with chronic liver disease have been explored – however, there remain conflicting data as to whether these T-cells are pathogenic or protective. In patients with some forms of liver disease, their expansion in the periphery and especially in the liver may indeed help pathogen clearance, while in other conditions their presence may, in contrast, contribute to disease progression. γδ T-cells can also express CD161, a C-type lectin, and such cells have been found to be involved in the pathogenesis of inflammatory disease. CD161+ T-cells of diverse subsets are known to be enriched in the livers of patients with chronic hepatitis C. This article serves to provide a review of the γδ T-cell population and its role in hepatitis C and other chronic liver diseases, and also explores a potential role of the CD161+ γδ T-cells in liver diseases.

Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study

Background and objectiveThe off-treatment durability of nucleos(t)ide analogue therapy in Asian hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) and the role of hepatitis B surface antigen (HBsAg)...

The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment

We investigated whether the quantification of hepatitis surface antigen (HBsAg) could predict HBsAg loss or hepatitis B virus (HBV) relapse after stopping lamivudine treatment. A total of 188 naive chronic hepatitis B patients (83 HBeAg-positive, 105 HBeAg-negative patients), who were previously treated with lamivudine (treatment duration: 89.3 ± 35.9 weeks, range: 52-243 weeks) but stopped the treatment for at least 12 months were recruited. The cumulative incidence of HBsAg loss and HBV relapse at year 6 after stopping lamivudine treatment was 24% and 65.9% respectively. Cox regression analysis revealed that lower alanine aminotransferase (ALT) at baseline, lower HBsAg levels at the end of treatment, and longer treatment duration were independent predictors for HBsAg loss, and old age, male sex and higher HBsAg levels at the end of treatment were independent predictors for post-treatment HBV relapse. At the end of treatment, the HBsAg cut-off value of 300 IU/ml could predict 55.6% (5/9) HBsAg loss in HBeAg-positive patients. In HBeAg-negative patients, the HBsAg cut-off values of 120 and 200 IU/ml could predict 79.2% (19/24) HBsAg loss and 93.3% (28/30) post-treatment sustained response respectively. Further HBsAg reduction (>0.22 log IU/ml) at month 6 after stopping treatment was an independent predictor for HBsAg loss after adjusting for HBsAg level at the end of treatment. Serum HBsAg level at the end of treatment is a useful predictor to guide the timing of stopping lamivudine treatment in chronic hepatitis B patients.

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

HBV-specific cytotoxic T-lymphocyte (CTL) activity has a very important role in hepatitis B virus clearance. Present studies suggest that Tapasin, a endoplasmic reticulum (ER) chaperone, stabilizes the peptide-receptive MHC I conformation, allowing peptide exchange and increasing more peptides to be translocated into the ER. We have previously testified that cytoplasmic transduction peptide (CTP)-HBcAg18–27-Tapasin fusion protein could enter cytoplasm of dendritic cells, and enhance T cells' response to generate specific CTLs efficiently in vitro. In the present study, we evaluated specific immune responses of CTP-HBcAg18–27-Tapasin fusion protein in HLA-A2 transgenic mice (H-2Kb) and anti-viral ability in HBV transgenic mice, and explored the mechanisms probably involved in. The studies showed that CTP-HBcAg18–27-Tapasin not only increased production of cytokine IFN-γ and interleukin-2 (IL-2), compared with CTP-HBcAg18–27, HBcAg18–27-Tapasin, and PBS, but also significantly induced the higher percentages of IFN-γ+CD8+ T cells and specific CTL responses in HLA-A2 transgenic mice. Moreover, enhancement of specific CTL activity induced by the fusion protein reduced HBV DNA and hepatitis B surface antigen (HBsAg) levels and decreased the expression of HBsAg and hepatitis B core antigen (HBcAg) in liver tissue of HBV transgenic mice. In addition, CTP-HBcAg18–27-Tapasin could upregulate the expression of JAK2, Tyk2, STAT1, and STAT4 in T lymphocytes in HLA-A2 transgenic mice splenocytes. However, there was no significant difference on the expressions of JAK1, JAK3, and STAT6 between each group. In conclusion, CTP-HBcAg18–27-Tapasin fusion protein could enhance not only the percentages of CTLs but also induce robust specific CTL activity and inhibits hepatitis B virus replication in vivo, which was associated with activation of the JAK/STAT signaling pathway.

Farnesyl‐diphosphate farnesyltransferase 1 regulates hepatitis C virus propagation

To identify the novel genes involved in lipid metabolism and lipid droplet formation that may play important roles in Hepatitis C virus (HCV) propagation, we have screened the small interfering RNA library using cell culture derived HCV (HCVcc)-infected cells. We selected and characterized the gene encoding farnesyl-diphosphate farnesyltransferase 1 (FDFT1). siRNA-mediated knockdown of FDFT1 impaired HCV replication in both subgenomic replicon and HCVcc infected cells. Moreover, YM-53601, an inhibitor of FDFT1 enzyme activity, abrogated HCV propagation. HCV infection increased FDFT1 protein level but not FDFT1 mRNA level. These results suggest that HCV may modulate FDFT1 protein level to facilitate its own propagation.

The deposition of Notch1 in hepatitis B virus‐associated nephropathy and its role in hepatitis B virus X protein‐induced epithelial–mesenchymal transdifferentiation and immunity disorder in renal tubular epithelial cells

Notch1 plays an important role in the regulation of immune responses and epithelial-mesenchymal transdifferentiation (EMT). Previous studies have observed inflammatory cell infiltration and tubulointerstitial fibrosis in the renal biopsies from patients with HBV-associated glomerulonephritis (HBV-GN). We hypothesized that Notch1 may be involved in the progression of HBV-GN. In this study, we evaluated the distribution of Notch1 in patients with HBV-GN. Our results showed that Notch1 was mainly distributed in renal tubules and the interstitial area, and the expression levels of Notch1 had a positive correlation with the renal tubular pathology. In this respect, we used human proximal tubular epithelial cells (HK-2) as target cells, which were transiently transfected with the hepatitis B virus X (HBx) gene using a eukaryotic vector. HBx expression resulted in significantly increased detection of Notch1, alpha-smooth muscle actin (α-SMA), major histocompatibility complex-II (MHC-II), CD40 and interleukin-4 (IL-4). At the same time, E-cadherin and interferon-γ (IFN-γ) expression levels were significantly inhibited. These HBx-induced phenotypes were exacerbated by upregulation of Notch1. Knock-down of Notch1 by specific shRNA caused decreases of α-SMA, MHC-II, CD40 and IL-4, and increases of E-cadherin and IFN-γ. These findings suggest that Notch1 is significantly associated with renal tubular and interstitial lesions. Notch1 can mediate HBx-induced EMT of HK-2 cells, promote HBx-induced increases in immune molecule expression and exacerbation of cytokine disorders, which may contribute to the progression of HBV-GN. Inhibitors of Notch1 signalling may be useful as new therapeutics for the treatment of HBV-GN.

Daclatasvir: potential role in hepatitis C [Corrigendum

Daclatasvir: potential role in hepatitis C [Corrigendum] Lee C. Drug Des Devel Ther. 2013;7:1223–1233. On page 1231 in the "Conclusion" section, line 3 contains incorrect information. The correct sentence is "This review summarizes key preclinical and clinical data of an HCV NS5A inhibitor, DCV, describing its discovery, mechanism of action, resistance profile, in vitro and in vivo efficacy and toxicity, and polymorphism."Read the original article

Extracellular adenosine controls NKT‐cell‐dependent hepatitis induction

Extracellular adenosine regulates inflammatory responses via the A2A adenosine receptor (A2AR). A2AR deficiency results in much exaggerated acute hepatitis, indicating nonredundancy of adenosine-A2AR pathway in inhibiting immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. An A2AR agonist abolished NKT-cell-dependent induction of acute hepatitis by concanavalin A (Con A) or α-galactosylceramide in mice, corresponding to downregulation of activation markers and cytokines in NKT cells and of NK-cell co-activation. These results show that A2AR signaling can downregulate NKT-cell activation and suppress NKT-cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-galactosylceramide induced more severe hepatitis in A2AR-deficient mice than in WT controls. Transfer of A2AR-deficient NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT-cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway.

An unbalanced PD-L1/CD86 ratio in CD14++CD16+ monocytes is correlated with HCV viremia during chronic HCV infection

Circulating monocyte subsets with distinct functions play important roles in hepatitis C virus (HCV) infection. However, the mechanisms have not been well studied. In this study, we analyzed the distributions and phenotypic characteristics of three circulating monocyte subsets-CD14(++)CD16(-), CD14(++)CD16(+) and CD14(+/dim)CD16(+)-in chronic HCV-infected patients, HCV spontaneous resolvers and healthy controls, and we evaluated the possible link between HCV viremia and disease progression. Our results indicated that the frequency of the CD14(++)CD16(+) monocyte subset was decreased, and negatively correlated with HCV RNA and core antigen levels during chronic HCV infection. PD-L1 expression and the PD-L1/CD86 ratio in CD14(++)CD16(+) monocytes were higher during chronic HCV infection than in spontaneous HCV resolvers and healthy controls. The PD-L1/CD86 ratio positively correlated with HCV viral load and core antigen levels. Finally, PD-L1 was significantly increased, while cytokine secretions were dramatically decreased upon Toll-like receptor (TLR) ligand binding and HCV JFH-1stimulation. These findings indicates the compromised immune status of the CD14(++)CD16(+) monocytes during chronic HCV infection and provides new insights into the specific role of the CD14(++)CD16(+) monocytes and their significance in chronic HCV infection.

Role of Hepatitis C Virus Induced Osteopontin in Epithelial to Mesenchymal Transition, Migration and Invasion of Hepatocytes

Osteopontin (OPN) is a secreted phosphoprotein which has been linked to tumor progression and metastasis in a variety of cancers including hepatocellular carcinoma (HCC). Previous studies have shown that OPN is upregulated during liver injury and inflammation. However, the role of OPN in hepatitis C virus (HCV)-induced liver disease pathogenesis is not known. In this study, we determined the induction of OPN, and then investigated the effect of secreted forms of OPN in epithelial to mesenchymal transition (EMT), migration and invasion of hepatocytes. We show the induction of OPN mRNA and protein expression by HCV-infection. Our results also demonstrate the processing of precursor OPN (75 kDa) into 55 kDa, 42 kDa and 36 kDa forms of OPN in HCV-infected cells. Furthermore, we show the binding of secreted OPN to integrin αVβ3 and CD44 at the cell surface, leading to the activation of downstream cellular kinases such as focal adhesion kinase (FAK), Src, and Akt. Importantly, our results show the reduced expression of epithelial marker (E-cadherin) and induction of mesenchymal marker (N-cadherin) in HCV-infected cells. We also show the migration and invasion of HCV-infected cells using wound healing assay and matrigel coated Boyden chamber. In addition, we demonstrate the activation of above EMT markers, and the critical players involved in OPN-mediated cell signaling cascade using primary human hepatocytes infected with Japanese fulminant hepatitis (JFH)-1 HCV. Taken together, these studies suggest a potential role of OPN in inducing chronic liver disease and HCC associated with chronic HCV infection.

Role of hepatitis C virus in B cell lymphoproliferations

Hepatitis C vires(HCV)constitutes a significant health burden worldwide,with an estimated 130-170 million people chronically infected.Severe liver disease,including advanced fibrosis,cirrhosis and hepatocellular carcinoma,is often a complication of long term infection,making HCV the most common in-

Role of hepatitis B virus DNA integration in human hepatocarcinogenesis.

Liver cancer ranks sixth in cancer incidence, and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which arises from hepatocytes and accounts for approximately 70%-85% of cases. Hepatitis B virus (HBV) frequently causes liver inflammation, hepatic damage and subsequent cirrhosis. Integrated viral DNA is found in 85%-90% of HBV-related HCCs. Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis. Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection. Integration has two potential consequences: (1) the host genome becomes altered ("cis" effect); and (2) the HBV genome becomes altered ("trans" effect). The cis effect includes insertional mutagenesis, which can potentially disrupt host gene function or alter host gene regulation. Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences. However, the role of integrated HBV DNA in hepatocarcinogenesis remains controversial. Modern technology has provided a new paradigm to further our understanding of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.

Investigation of interleukin-18 polymorphism in hepatit B virus carriers, chronic hepatitis and cirrhosis patients

Objective: IL-18 has been shown to play a protective role in the host defense towards different sources of infection or to have a pathological role in hepatitis B (HBV). Methods: For the purposes of this study, we analyzed IL-18 single-nucleotide polymorphisms (SNPs) in hepatitis B virus carrier, chronic hepatitis, cirrhosis, and non-infected individuals. Presence of the IL-18 genotyping was performed using the PCR amplification and DNA sequencing. Results: Significant associations were detected between the IL-18 rs187238 (G/C) polymorphism and infected patients. Conclusion: Based on our data, there were no significant associations between the IL-18 rs61667799(G/T), rs5744227(C/G), rs5744228(A/G) polymorphism in Turkish HBV infected and non-infected individuals with HBV.

Factors Associated with Persistence of Hepatitis B Virus Infection

Hepatitis B Virus (HBV) infection is a global health problem that is endemic in many parts of the world. 90-95% of the infected adults can clear the virus. Host genetic factors play a major role in determining the outcome of HBV infection. This study estimated the role of nonfunctional CCR5 receptor (CCRΔ32 mutation) in the recovery from hepatitis B infection among Georgian patients. Case-control study has been conducted, where study subjects with persistent HBV infection were matched to double number of individuals who had recovered from the HBV infection. The overall number of study subjects was 282 (94 cases and 188 controls). Demographic, medical and behavioral characteristics of the study participants were collected. CCR5 delta32 mutation was evaluated by PCR methodology. The overall prevalence of CCR5 receptor mutation was 13.1% (n=37). Among controls (HBsAg-) CCR5 receptor mutation was detected in 16.5% (n=31), in cases - only in 6.4% (n=6). Cases were 2.58 times less likely to have CCR5 Δ32 mutation compared to controls (OR =2.58; 95% CI 1.12, 5.98). Multivariate analysis revealed CCR5 receptor mutation and alcohol consumption as independent predictors of HBs positivity. The study gives clear evidence that genetic factors (CCR5 receptor mutation) play an important role in Hepatitis B virus persistence together with environmental/behavioral factors, such as the alcohol use.

Type 2 Diabetes Mellitus and Hepatitis C are Unlikely Contributors in a Case of Progression of Diabetic Nephropathy to End Stage Renal Disease

Progression of diabetic nephropathy to end stage renal disease can occur in the presence of minimal evidence for type 2 diabetes mellitus, and the recent literature indicates the pathology of diabetic nephropathy arises even in the absence of diabetes, suggesting other contributors like over expression of glucose transporter 1 (GLUT1) may have a similar pathogenesis. Although hepatitis C has been implicated in accelerating declines of renal function in diabetic nephropathy in some cases, evidence of hepatitis C activity cannot be assumed to contribute to the worsening renal function in this case. Here we report a case in a 61 year- old female with minimal elevation of Hemoglobin A1C (HbA1C), seropositivity for hepatitis C and anapparent rapid decline of renal function. The patient presented with a previous elevation of serum creatinine concentration from 1.4 to 4.7 mg/dl over the last 23 months. The patient had been treated with insulin and a recent HbA1C was 6.2%, correlating with an average blood glucose concentration of 130-150 mg/dl. There was no history of diabetic retinopathy or neuropathy. The patient was also taking anangiotensin converting enzyme inhibitor (ACEI) and had controlled hypertension over the 2 years prior to the current hospitalization for hematochezia. The serum creatinine then increased to nearly 6 mg/ dl after admission. Acute kidney injury work-up (super imposed on chronic kidney disease and proteinuria) beyond hematochezia, revealed hepatitis C seropositivity without liver failure. The renal biopsy was typical for established diabetic glomerulosclerosis, without evidence of another disease process. A plot of the reciprocal serum creatinine concentration versus time waned linearly as expected for progression of a single, chronic disease process, despite the appearance of promptly falling renal function on the plot of serum creatinine concentration versus time. We suggest that 1) The appearance of rapid decline ofrenal function was actually the natural progression of chronic diabetic nephropathy; 2) Other contributors rather than mild level of hyperglycemia might associated with development of substantial diabetic nephropathy despite clinical absence of other diabetic tissue complications; 3) A role for hepatitis C -persuaded acceleration of renal disease was not supported in this case.

Purinergic signaling via P2Y receptors up-mediates IL-6 production by liver macrophages/Kupffer cells.

Resident macrophages in the liver (Kupffer cells) produce various cytokines and chemokines, and have important roles in hepatitis and liver fibrosis. The cells are activated by various factors, for example lipopolysaccharide (LPS), which is an endotoxin and is high in the blood of patients with liver cirrhosis. Involvement of P2 receptors in the release of pro-inflammatory cytokines from Kupffer cells is little. In this study, we investigated purinergic signaling in the release of pro-inflammatory cytokines, such as IL-6 and TNF-α, from liver Kupffer cells of C57BL/6 mice (KUP5 cells). KUP5cells were isolated from C57BL/6 mice and cultivated with Dulbecco's modified Eagle's medium. The cells were stimulated with LPS. LPS-induced IL-6 production by KUP5 cells was suppressed significantly by pretreatments with non-selective P2 antagonist suramin, P2Y13antagonist MRS2211, and ecto-nucleotidase, whereas P2Y receptor agonists, significantly increased the IL-6 production. P2Y13knockdown reduced LPS-induced IL-6 production, but by less than 50%. These results would suggest that P2Y receptors including P2Y13and others, may involves in LPS-induced IL-6 production in Kupffer cells, leading to the liver inflammation. Therefore, we first showed the importance of purinergic signaling via P2Y receptors in the activation of Kupffer cells and liver injury, which is worthwhile in drug development for liver diseases.

Current Information Concerning Association of IL-12 and Hepatitis B Infection

Hepatitis B is one of the most prevalent infectious diseases and is induced by hepatitis B virus (HBV). The chronic, asymptomatic, and occult forms of hepatitis B are long-term infections that can lead to various hepatic cancers and cirrhosis in the carrier. IL-12 is one of the main cytokines involved in inducing appropriate immune responses against viral infections, especially HBV. Therefore, the aim of the present review was to address the most recent information within the database regarding the status and association between IL-12 and hepatitis B infection and its complications including cirrhosis and hepatocellular carcinoma. The data presented was collected by searching the following keywords in the Pubmed and Scopous databases: Hepatitis B, occult HBV infection, chronic HBV infection, asymptomathic HBV infection, acute HBV infection, fulminant HBV infection, IL-12, and all the papers regarding the relation between IL-12 and hepatitis B were used. These data were presented in the current review article. Results showed that IL-12 plays important roles in Hepatitis B infection and patients infected with the long-term form of hepatitis B are unable to produce sufficient amount of this cytokine. Our research provided mechanistic insights into the immunoprotective roles of IL-12 and proposed that it can be considered as an important molecule for immunotherapy of HBV infected infection.

Role of hepatitis B virus integration in evolution of hepatocellular carcinoma

Hepatitis B virus(HBV)-human DNA integration is a commonly seen event in the evolutionary process of hepatocellular carcinoma(HCC).HBV chronic infection induces HBV mutation,HBV integration and the inflammatory microenvironment alternation in the hosts,which provides a evolutionary soil for the hepatocarcinogenesis.The second generation sequencing technique provides a better approach for understanding the HBV integration mechanism in HCC.This review focuses on the features of HBV integration and influences of HBV integration on human,virus genomes,and discusses the association of HBV integration with HCC.

The Role of Hepatitis B Surface Antigen Level in Correlation with Viral Load in Untreated Patients with Chronic Hepatitis B in Ramadi City , West of Iraq

The Role of Hepatitis B Surface Antigen Level in Correlation with Viral Load in Untreated Patients with Chronic Hepatitis B in Ramadi City , West of Iraq

The association of chronic hepatitis B virus infection and the risk and prognosis of intrahepatic cholangiocarcinoma

Currently,there is a worldwide increase in the incidence and mortality of intrahepatic cholangiocarcinoma (ICC),but the etiology of ICC remains unclear.Recent efforts suggest an etiological role of hepatitis B virus (HBV)infection in ICC,and this article reviews the relationship between chronic HBV infection and the risk and prognosis of ICC. Key words: Bile duct neoplasms; Hepatitis B virus