Yingren Zhao

The balance between intrahepatic IL-17+ T cells and Foxp3+ regulatory T cells plays an important role in HBV-related end-stage liver disease

BackgroudIL-17+ T helper cells and Foxp3+ regulatory T cells are CD4+ T helper cells with reciprocally regulated differentiation and function. Their frequency and function vary in patients with chronic hepatitis B. In this study, we investigated the balance between IL-17+ T cells and Foxp3+ regulatory T cells and illustrated their function in the aggravation of chronic hepatitis B (CHB).ResultsTwenty-six patients with chronic HBV -related liver failure (CLF), thirty-one patients with acute on chronic HBV-related liver failure (ACLF) and twelve normal controls were enrolled in our study. The expressions of IL-17, Foxp3, CD4, CD8 and perforin in liver tissue were measured by immunochemistry for the evaluation of liver-infiltrating lymphocytes. The frequency of liver IL-17+ T cells on liver inflammatory cells and their proportion in the total CD4+ T cell population increased markedly in the ACLF group, while the frquency of Foxp3+ T cells and their proportion in the total CD4+ T cell population did not show a significant difference in the two HBV infection groups. In addition, the ACLF group showed a dramatically higher IL-17+ /Foxp3+ ratio than the CLF group. CD4+ T cells increased significantly in the liver of patients with ACLF, compared with those in the liver of patients with CLF.ConclusionsOur findings suggest that intrahepatic IL-17+ T cells play an important role in the development of chronic HBV and that the imbalance between IL-17+ and Foxp3+ T cells in the liver may lead to progression of the disease but the mechanism should be further explored.

Correlation of TLR1-10 expression in peripheral blood mononuclear cells with chronic hepatitis B and chronic hepatitis B-related liver failure

Toll-like receptors (TLRs) promote host defenses against invading viruses and pathogenic bacteria through corresponding adapter molecules leading to the initiation of innate immune response. We investigated the expression of TLR1-10 in peripheral blood mononuclear cells (PBMCs) from patients with different clinical phases of chronic hepatitis B (CHB) infection and analyzed the correlation between TLRs and clinical profiles. Our results showed that expression of TLR3/5/7/9/10 and TLR2/4/6 mRNA was upregulated in active stage of CHB and CHB-related liver failure, respectively. Particularly we found that TLR9 mRNA expression is negatively correlated with serum alanine aminotransferase (ALT), Tbil, PTA, and positively correlated with hepatitis B virus (HBV) viral load in CHB patients. Our results indicate that innate immune responses are significantly higher in CHB active phase than that in CHB-related liver failure, suggesting TLRs may play a critical role in development of CHB and CHB-related liver failure, the mechanisms need further to be further explored.

Correlation of AIM2 expression in peripheral blood mononuclear cells from humans with acute and chronic hepatitis B

The AIM2 (absent in melanoma 2) protein promotes host defenses against invading viruses and pathogenic bacteria through corresponding adapter molecules leading to the initiation of innate immune responses. We investigated the expression of AIM2 in peripheral blood mononuclear cells (PBMCs) from patients with acute hepatitis B (AHB) and chronic hepatitis B (CHB) during different clinical phases, and analyzed the correlation between AIM2 and clinical profiles in these groups. This study indicated that there is higher expression of AIM2, IL-1β, and IL-18 in AHB compared with expression in CHB. The expression of AIM2 mRNA was significantly negatively correlated with serum hepatitis B virus (HBV) load, HBeAg, and significantly positively correlated with IL-1β and IL-18 in AHB patients and CHB patients with immune clearance, which suggests that AIM2 expression is correlated with the immune clearance of HBV in the host. We summarized that there is a higher immune status in AHB, and a lower immune response in CHB. This suggests that the down-regulation of AIM2 may be associated with the chronic development of HB.

An early decrease in serum HBeAg titre is a strong predictor of virological response to entecavir in HBeAg‐positive patients

Summary.  Quantification of HBeAg levels has been found to be useful in monitoring and predicting the outcomes of interferon and lamivudine treatment in HBeAg‐positive patients. The aim of this study was to determine whether quantification of HBeAg at baseline and on treatment could predict which patients would achieve HBeAg seroconversion after 96 weeks of entecavir therapy. Sixty‐five HBeAg‐positive naïve chronic hepatitis B patients who were treated with entecavir at a dose of 0.5 mg once daily for 96 weeks were evaluated. Serum HBV DNA levels were assessed at baseline, week 24, 48 and 96; serum HBeAg levels were assessed at baseline, week 12, 24, 48, 72 and 96. Serum HBeAg levels were associated with a higher likelihood of HBeAg seroconversion to entecavir at weeks 96 than serum HBV DNA levels both at baseline and on treatment (at baseline: OR = 9.932, P = 0.003 vs OR = 5.045, P = 0.036; on treatment: OR = 112.5, P < 0.0001 vs OR = 47.782, P < 0.0001). A maintained reduction in HBeAg > 65% of pretreatment HBeAg values after 24 weeks of entecavir therapy is the strongest predictor for HBeAg seroconversion at week 96 (OR = 70.578, P < 0.0001). Quantification of HBeAg at the start and early during therapy showed a higher predictive value than that of HBV DNA for HBeAg seroconversion by entecavir. A significant decrease in serum HBeAg levels at week 24 may be a useful on‐treatment measurement in the early phase for predicting HBeAg seroconversion and identifying patients who will most likely benefit from finite entecavir treatment.

Asialoglycoprotein receptor interacts with the preS1 domain of hepatitis B virus in vivo and in vitro

BackgroundThe preS1 domain of the large envelope protein has been identified as an essential viral structure involved in hepatitis B virus (HBV) attachment. However, the cellular receptor(s) for HBV has not yet been identified. AimsTo identify a cell-surface receptor for HBV, which could elucidate the molecular mechanism of HBV infection.MethodsA novel yeast two-hybrid system was used to screen proteins interacting with the preS1 region of HBV. Their interaction was verified by yeast cotransformation, coimmunoprecipitation and mammalian two-hybrid assay, while their intracellular and tissue localization was analyzed by confocal microscopy and immunohistochemistry, respectively.ResultsAsialoglycoprotein receptor (ASGPR) interacted specifically and directly with the preS1 domain of HBV in vivo and in vitro. The levels of expression of preS1 and ASGPR in the liver were similar and correlated with each other. ConclusionsASGPR is a candidate receptor for HBV that mediates further steps of HBV entry.

Restoring the Treg cell to Th17 cell ratio may alleviate HBV-related acute-on-chronic liver failure

AIM To investigate the role of T helper 17 cells (Th17) and regulatory T cells (Treg) in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS We enrolled 79 patients with HBV infection into the study, 50 patients with HBV-related ACLF and 29 patients with chronic hepatitis B (CHB), from the First Affiliated Hospital of Medical College from January 2009 to June 2012. The ACLF patients were diagnosed according to the criteria recommended by The 19(th) Conference of the Asian Pacific Association for the Study of the Liver in 2009. Twenty healthy individuals with a similar gender and age structures to the two patient groups were also included as the normal controls (NC). Of the 50 ACLF patients, 28 were subsequently classified as non-survivors: 19 patients died from multi-organ failure, 3 underwent liver transplantation, and 6 discontinued therapy during follow-up because of financial reasons. The remaining 22 ACLF patients whose liver and anticoagulation function recovered to nearly normal levels within the next 6 mo were classified as survivors. The number of circulating Treg and Th17 cells was determined upon diagnosis and during the 8th week of follow-up through flow cytometry. RESULTS The percentage of circulating Treg cells in the ACLF group was significantly higher than that in the CHB group (5.50% ± 1.15% vs 3.30% ± 1.13%, P < 0.01). The percentages of circulating Th17 cells in the ACLF and the CHB groups were significantly higher than that in the NC group (6.32% ± 2.22% vs 1.56% ± 0.44%, P < 0.01; 3.53% ± 1.65% vs 1.56% ± 0.44%, P < 0.01). No significant difference in Treg cell to Th17 cell ratio was observed between the ACLF group and the CHB group (0.98 ± 0.44 vs 1.12 ± 0.64, P = 0.991), whereas those in the two HBV infection groups were significantly lower than that in the NC group (1.85 ± 1.22; both P < 0.01). The percentage of Treg cells in the survivors during the 8(th) week of follow-up was significantly lower than that during peak ACLF severity [total bilirubin (TBIL) peak] (3.45% ± 0.97% vs 5.18% ± 1.02%, P < 0.01). The percentage of Th17 cells in survivors during the 8(th) week of follow-up was significantly lower than that during the peak TBIL (2.89% ± 0.60% vs 5.24% ± 1.46%; P < 0.01). The Treg cell to Th17 cell ratio during the 8(th) week of follow-up was significantly higher than that during the TBIL peak (1.22 ± 0.36 vs 1.10 ± 0.54; P < 0.05). CONCLUSION Restoring the Treg cell to Th17 cell ratio during the follow-up phase of ACLF could maintain the immune system at a steady state, which favours good prognosis.

Mechanisms of fibrosis in acute liver failure

Acute liver failure (ALF) is a condition with high mortality and morbidity. Fibrosis in chronic liver disease was extensively researched, whereas fibrosis and underlying mechanism in acute liver failure remains unclear.

Hepatic flare after telbivudine withdrawal and efficacy of postpartum antiviral therapy for pregnancies with chronic hepatitis B virus

The efficacy of telbivudine for breaking vertical transmission of hepatitis B virus has been well established. Data on the risk of postpartum flare after telbivudine withdrawal and efficacy of extended antiviral therapy after delivery are limited.

17β-Estradiol Suppresses the Macrophage Foam Cell Formation Associated with SOCS3

Evidence from clinical trials and animal experiments has shown that estrogen has anti-atherosclerotic effects when administered to young women or experimental animals. The mechanisms involve the modulation of vascular inflammation, growth factor expression, and oxidative stress injured arteries. However, whether estrogen modulates the foam cell formation in plaque remains unknown. Here, we investigated the effects of 17β-estradiol (E2) on cholesterol efflux in vivo and in vitro. ApoE null mice underwent an ovariectomy at 5(th) week of age and then were treated with E2 or vehicle for the following 8 weeks. Compared with the vehicle-treated mice, the serum total cholesterol level, atherosclerotic plaque size, and lipid deposits were decreased and meanwhile ATP-binding cassette transporter A1 (ABCA1) expression in the plaque was increased in mice with E2 treatment. E2 also increased suppressor of cytokine signaling 3 (SOCS3) expression in the atherosclerotic plaques and in RAW264.7 cells. In vitro, E2 treatment reversed janus kinase/signal transducers and activators of transcription (JAK/STAT)-inhibited ABCA1 expression in RAW264.7 cells but had no effect on ABCA1 expression in SOCS3 knockdown cells. SOCS3 overexpression elevated ABCA1 expression through the inhibition of JAK2/STAT3 phosphorylation. Finally, we also found that E2 enhanced the cholesterol efflux to apoA I in RAW264.7 cells. In summary, E2 reduces atherosclerosis in ApoE null mice associated with upregulating ABCA1 expression and modulating the cholesterol efflux, which are dependent on SOCS3 upregulation. These results provide new insight into the athero-protective effects of estrogen.

Hepatic flare after telbivudine withdrawal and efficacy of postpartum antiviral therapy for pregnancies with chronic HBV.

The efficacy of telbivudine for breaking vertical transmission of hepatitis B virus has been well established. Data on the risk of postpartum flare after telbivudine withdrawal and efficacy of extended antiviral therapy after delivery are limited.