Chronic hepatitis B is caused by persistent infection with the hepatitis B virus (HBV), a unique DNA virus that replicates through an RNA intermediate produced from a stable covalently closed circular DNA molecule. Viral persistence appears to be due to inadequate innate and adaptive immune responses. Chronic infection has a variable course after several decades resulting in cirrhosis in up to one‐third of patients and liver cancer in a proportion of those with cirrhosis. Sensitive assays for HBV DNA levels in serum have been developed that provide important insights into pathogenesis and natural history. Therapy of hepatitis B is evolving. Peginterferon induces long‐term remissions in disease in one‐third of patients with typical hepatitis B e antigen (HBeAg) positive chronic hepatitis B, but a lesser proportion of those without HBeAg. Several oral nucleoside analogues with activity against HBV have been shown to be effective in suppressing viral levels and improving biochemical and histological features of disease in a high proportion of patients with and without HBeAg, at least in the short term. What is uncertain is which agent or combination of agents is most effective, how long therapy should last, and which criteria should be used to start, continue, switch or stop therapy. Long‐term therapy with nucleoside analogues may be the most appropriate approach to treatment, but the expense and lack of data on long‐term safety and efficacy make recommendations difficult. Clearly, many basic and clinical research challenges remain in defining optimal means of management of chronic hepatitis B. (HEPATOLOGY 2007;45:1056–1075.)

Management of hepatitis B: Summary of a clinical research workshop Potential conflict of interest: Dr. Lok is a consultant and received grants from GlaxoSmithKline, Bristol-Myers Squibb, Idenix, Gilead, Roche, and Innogenetics.

Background
Hepatitis B virus-related liver fibrosis (HBV-LF) always progresses from inflammation to fibrosis. However, the relationship between these two pathological conditions is not fully understood. Here, it is postulated that the balance between regulatory T (Treg) cells and T helper 17 (Th17) cells as an indicator of inflammation may predict fibrosis progression of HBV-LF.

Significance of the balance between regulatory T (Treg) and T helper 17 (Th17) cells during hepatitis B virus related liver fibrosis.

Importance of the field: Hepatic cirrhosis is a frequent consequence of chronic hepatitis infection (HBV and HCV) or alcohol abuse and the most common cause of hepatocellular carcinoma (HCC). Currently, liver transplantation remains the only effective therapeutic approach for cirrhosis-related HCC patients. The evolution of the pathology strongly depends on immunological mechanisms. Areas covered in this review: Despite the presence of specific T cells, viral chronic infection and continuous tumor growth suggest a failure of immune control. It appears that direct suppression of antiviral or antitumor effector cells by regulatory T cells plays a pivotal role in the impairment of immune response. Several types of regulatory T cells have been described, natural regulatory T cells (nTreg) and induced-type 1 regulatory T cells (Tr1) being the best characterized. What the reader will gain: Currently, there is no evidence for a direct implication of regulatory T cells in the evolution of hepatitis, especially co...

Regulatory T cells in HBV and HCV liver diseases: implication of regulatory T lymphocytes in the control of immune response.

Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge experimental approaches have demonstrated key pathways that involve cross-talk between viral particles and host immune cells. All events, including penetration of hepatitis B virus (HBV) particles into host cells, establishing persistence, and chronization of CHB infection, and possibility of complete elimination of HBV particles are controlled by the immune system. Researchers have paid special attention to the replication capacity of HBV in host cells, which is associated with cellular changes that reflect presentation of viral antigens and variability of HBV antigen features. In addition, specific HBV proteins have an immune-modulating ability to initiate molecular mechanisms that "avoid" control by the immune system. The relationship between immunological shifts and chronic infection stages has been intensively studied since it was recognized that the immune system is a direct participant in the recurrent (cyclic) nature of CHB. Understanding the wide diversity of molecular pathways and the crosstalk between innate and adaptive immune system components will provide fresh insight into CHB immune pathogenesis and the possibilities of developing new treatment strategies for this disease.

Immunopathogenesis of chronic hepatitis B

B- and T-lymphocyte attenuator (BTLA) is an immune-regulatory receptor, similar to CTLA-4 and PD-1, and is mainly expressed on B-, T-, and all mature lymphocyte cells. Herpes virus entry mediator (HVEM)-BTLA plays a critical role in immune tolerance and immune responses which are areas of intense research. However, the mechanisms of the BTLA and the BTLA/HVEM signaling pathway in human diseases remain unclear. This review describes the research milestones of BTLA and HVEM in chronological order and their role in chronic HBV infection.

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BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection

The roles of regulatory T cells (Tregs) and PD-1 in hepatitis B have not been clearly described. Also, the role of B and T lymphocyte attenuator (BTLA), which serves as a negative regulator of T-cell activation, is still unknown in hepatitis B. In this study, we analyzed the frequency of circulating CD4(+)CD25(high) Tregs in patients with chronic hepatitis B (CHB), and subsequently investigated expression of PD-1 and BTLA on CD4(+) T cells, as well as their relationships with the clinical index of CHB patients. A total of 39 CHB patients and 19 healthy persons as controls were enrolled in the study. We found that the frequency of CD4(+)CD25(high) Tregs and PD-1 expression on CD4(+) T cells was significantly increased in CHB patients compared with normal controls. However, BTLA expression on CD4(+) T cells showed no significant difference between the two groups. The frequency of Tregs was significantly higher in patients with HBV DNA titers >or=10(8) than in those with HBV DNA titers <10(8). Circulating CD4(+)CD25(high) Treg frequency and PD-1 expression on CD4(+) T cells correlated positively with serum HBV DNA load in CHB patients. Our findings suggest that the increased frequency of CD4(+)CD25(high) Tregs and PD-1 expression on CD4(+) T lymphocytes may inhibit the cellular immune response against HBV and affect viral clearance, leading to the persistence of chronic HBV infection.

Circulating CD4+CD25high regulatory T cells and expression of PD-1 and BTLA on CD4+ T cells in patients with chronic hepatitis B virus infection.

Chronic hepatitis B is characterized by an impaired immune response to hepatitis B virus (HBV). Telbivudine treatment has significantly improved the clinical outcome of chronic HBV infection. However, the underlying mechanism behind the antiviral response of patients treated with nucleoside analogs remains unclear. To gather more evidence about the mechanism responsible for the weak immune response, in this study we analyzed the effects on HBV viral load of treatment with the nucleoside analogue telbivudine and the percentage of Tregs, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, and related cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum of 28 patients with chronic hepatitis B were collected at baseline, and 3 mo and 6 mo after therapy was begun. In parallel with the decline in viral load and serum ALT normalization, we found a decline in circulating CD4+CD25high Tregs, PD-L1 on CD4+ T cells, and IL-9 production. The expression of PD-1 on CD4+...

Inhibition of Viral Replication Downregulates CD4+CD25high Regulatory T Cells and Programmed Death-Ligand 1 in Chronic Hepatitis B

Sludge dewatering is a necessary process in the disposal of waste activated sludge (WAS). In this study, thermally activated sodium persulfate–biochar skeleton pretreatment was performed to improve the dewaterability of sludge, and its internal mechanism was systematically elucidated. The experimental results showed that, under optimal operating conditions, the water content of WAS could be reduced from 89.7% to 61.3% of the raw sludge. Under these conditions, the capillary suction time and specific resistance to filtration were roughly 23.23% and 59.57% of those in the raw sludge, respectively. This study proposes a relationship between organic matter migration and sludge physical structure that explains the dewaterability improvement mechanism. Separate thermal treatment caused organic matter such as proteins, polysaccharides, and humic substances to dissolve, releasing their bound water. Simultaneously, changes in the surface structure (pore size reductions and BET surface area increases) deteriorated the dewaterability of WAS. The reactive oxygen species generated by the thermally activated sodium persulfate further mineralized the organic matter, simplifying the floc surface structure (pore size increases and BET surface area decreases) and finally improving the dewaterability. Under these conditions, the addition of biochar increased the pore size, and further improved sludge dewaterability. 

Mechanism of thermally activated sodium persulfate–biochar skeleton treatment to improve the dewaterability of waste activated sludge

In this paper, the change characteristics of DOM (dissolved organic matter) and acid production characteristics of anaerobic fermentation in waste activated sludge(WAS) pretreated with rhamnolipid (RL) were studied. The results showed that RL at the dose of 80 mg/gTS could significantly promote the disintegrating of EPS (extracellular polymers) and cell wall in WAS, and a large number of proteins and carbohydrates were dissolved. Three dimensional fluorescence parallel factor analysis showed that the addition of RL enhanced the dissolution and biodegradability of humus-like substances. LC-OCD (Liquid chromatography - organic carbon detection ) analysis showed that RL promotes the dissolution of biodegradable components such as Biopolymer, Building Blocks and LMW Neutrals, and ensures the increase of VFA (volatile fatty acids) production in the process of anaerobic fermentation. Under the RL dose of 80 mg/gTS, the maximum VFA production of WAS was obtained at 108 h of anaerobic fermentation, which was 2699.39 mg/L. Acetic acid and propionic acid were the main components in the WAS fermentation broth pretreated by RL. The concentration of butyric acid increased with the increase of RL dose. The RL dose can significantly affect the composition of VFA in WAS fermentation broth.

Rui-Lin Sun

Papers

Circulating CD4+CD25high regulatory T cells and expression of PD-1 and BTLA on CD4+ T cells in patients with chronic hepatitis B virus infection.

Inhibition of Viral Replication Downregulates CD4+CD25high Regulatory T Cells and Programmed Death-Ligand 1 in Chronic Hepatitis B

Mechanism of thermally activated sodium persulfate–biochar skeleton treatment to improve the dewaterability of waste activated sludge

Effects of rhamnolipid pretreatment on DOM dissolution characteristics and anaerobic fermentation acid production of waste activated sludge.