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Th17 cells are involved in liver fibrosis by activating hepatic stellate cells (HSCs). We aimed to investigate whether HSCs are able to regulate the function of Th17 cells and to determine the relevant mechanism. Sixty-five patients diagnosed with chronic hepatitis B (CHB) were enrolled in this study. To determine the effect of HSCs on T cells, naïve CD4 + T cells and Th17 cells were sorted from CHB patients and cultured with or without activated-HSCs, and cytokine expression and gene transcription were analyzed. In addition, the regulatory mechanism of HSCs was investigated. ELISA and qRT-PCR showed that Th17 cells from CHB patients were more pathogenic, on the basis of the expression of IL-17A, IL-23R, RORC, CCL20 and CCR6, and meanwhile, they could activate the primary HSCs. Co-culture experiments indicated that activated HSCs dramatically promoted proliferation of CD4 + T cells in a time- and dose-dependent manner. In addition, they could induce naïve CD4 + T cells to become Th17 cells which had a more pathogenic phenotype. Moreover, activated HSCs-mediated induction of Th17 cells might depend on the release of IL-1β and IL-6 as well as on the COX-PGE2 pathway. Th17 cells cooperated with HSCs in a proinflammatory feedback loop might provide a better understanding of the pathogenic role of Th17 cells in the chronicity of HBV infection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., Methodology/principal Findings: The frequencies and phenotypes of peripheral Treg and Th17 cells of seventy-seven HBeAg-positive chronic hepatitis B (CHB) patients who underwent liver biopsies and thirty healthy controls were determined by flow cytometry. In the periphery of CHB patients, both Treg and Th17 frequencies were significantly increased and correlated, and a lower Treg/Th17 ratio always indicated more liver injury and fibrosis progression. To investigate exact effects of Treg and Th17 cells during HBV-LF, a series of in vitro experiments were performed using purified CD4(+), CD4(+)CD25(+), or CD4(+)CD25(-) cells from the periphery, primary human hepatic stellate cells (HSCs) isolated from healthy liver specimens, human recombinant interleukin (IL)-17 cytokine, anti-IL-17 antibody and HBcAg. In response to HBcAg, CD4(+)CD25(+) cells significantly inhibited cell proliferation and cytokine production (especially IL-17 and IL-22) by CD4(+)CD25(-) cells in cell-contact and dose-dependent manners. In addition, CD4(+) cells from CHB patients, compared to those from HC subjects, dramatically promoted proliferation and activation of human HSCs. Moreover, in a dramatically dose-dependent manner, CD4(+)CD25(+) cells from CHB patients inhibited, whereas recombinant IL-17 response promoted the proliferation and activation of HSCs. Finally, in vivo evidence about effects of Treg/Th17 balance during liver fibrosis was obtained in concanavalin A-induced mouse fibrosis models via depletion of CD25(+) or IL-17(+) cells, and it's observed that CD25 depletion promoted, whereas IL-17 depletion, alleviated liver injury and fibrosis progression., Conclusions/significance: The Treg/Th17 balance might influence fibrosis progression in HBV-LF via increase of liver injury and promotion of HSCs activation.

Summary: Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates. [ABSTRACT FROM AUTHOR]

Antiviral therapy is important in patients with hepatitis B virus ( HBV)-related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child-Pugh or model for end-stage liver disease ( MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir ( ETV) or tenofovir disoproxil fumarate ( TDF) is the first-line therapy for nucleos(t)ide analogue ( NA)-naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug-resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma ( HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug-resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV-related cirrhosis and a long-term follow-up in China, where a large number of such patients are found, are recommended. [ABSTRACT FROM AUTHOR]

Background & Aims Distinguishing between acute on chronic liver failure (ACLF) and decompensated liver cirrhosis is difficult due to a lack of pathological evidence. Methods A prospective single-center study investigated 174 patients undergoing liver transplantation due to acute decompensation of hepatitis B virus (HBV)-associated liver cirrhosis. Two groups were distinguished by the presence or absence of submassive hepatic necrosis (SMHN, defined as necrosis of 15–90% of the entire liver on explant). Core clinical features of ACLF were compared between these groups. Disease severity scoring systems were applied to describe liver function and organ failure. Serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes were used to study systemic and local inflammatory responses. Results SMHN was identified in 69 of 174 patients proven to have cirrhosis by histological means. Characteristic features of SMHN were extensive necrosis along terminal hepatic veins and spanning multiple adjacent cirrhotic nodules accompanied by various degrees of liver progenitor cell-derived regeneration, cholestasis, and ductular bilirubinostasis. Patients with SMHN presented with more severely impaired hepatic function, a higher prevalence of multiple organ failure (as indicated by higher CLIF-SOFA and SOFA scores) and a shorter interval between acute decompensation and liver transplantation than those without SMHN ( p <0.01 for all parameters). Further analyzes based on serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes revealed higher levels of anti-inflammatory cytokines in patients with SMHN. Conclusions SMHN is a critical histological feature of HBV-associated ACLF. Identification of a characteristic pathological feature strongly supports that ACLF is a separate entity in end-stage liver disease. [ABSTRACT FROM AUTHOR]