History of tuberculosis

Toll-like receptors (TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte (i.e., hepatocellular injury and regeneration) or hepatic stellate cell (i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.

Toll-like receptors in pathophysiology of liver diseases

Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in host defence by recognizing pathogen-associated molecular patterns (PAMP). Recent studies indicate that TLR signalling plays an important role in progression of chronic liver diseases. Ongoing clinical trials suggest that therapeutic manipulation of TLR pathways may offer novel means of reversing chronic liver diseases. Upon activation by their respective ligands, TLRs initiate an intracellular pro-inflammatory/anti-inflammatory signalling cascade via recruitment of various adaptor proteins. TLR associated signalling pathways are tightly regulated to keep a check on inappropriate production of pro-inflammatory cytokines and interferons thereby preventing various autoimmune and inflammatory processes. Herein, we review the current state of knowledge of hepatic distribution, signalling pathways and therapeutic modulation of TLRs in chronic liver diseases.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/liv.12315

Toll-like receptors and liver disease.

Background Hepatic stellate cell (HSC) plays a key role in pathogenesis of liver fibrosis. During liver injury, hypoxia in local micro-environment is inevitable. Hif-1α is the key transcriptional regulation factor that induces cell's adaptive responses to hypoxia. Recently, it was reported that MAPK is involved in regulation of Hif-1α activity. Aims To explore whether Hif-1α regulates HSC activation upon hypoxia, and whether MAPK affects Hif-1α-regulated signaling cascades, thus providing new targets for preventing liver fibrosis. Methods Hif-1α expression in livers of Schistosomajaponicum infected BALB/c mice was detected with western blot and immunohistochemistry. A rat cell line of HSC, HSC-T6, was cultured in 1% oxygen. HSC activation, including F-actin reorganization, increase of vimentin and α-SMA, was detected with western blot or immunocytochemistry. Cells were transfected with specific siRNA to Hif-1α, expression of activation markers, transcription of fibrosis-promoting cytokines, secretion of collagen I were detected with western blot, Real Time PCR and ELISA. Lysate from HSC-T6 cells pretreated with PD98059, a specific MEK1 pharmacological inhibitor, was subjected to detect Hif-1α ubiquitination and nuclear translocation with western blot and immunoprecipitation. Results and conclusions Hif-1α apparently increased in liver tissues of Schistosomajaponicum infected mice. 1% O2 induced F-actin reorganization, increase of Hif-1α, vimentin and α-SMA in HSC-T6 cells. Hif-1α Knockdown inhibited HSC-T6 activation, transcription of IL-6, TGF-β and CTGF and secretion of collagen I from HSC-T6 cells upon hypoxia. Inhibition of MAPK phosphorylation enhanced Hif-1α ubiquitination, and inhibited Hif-1α translocation into nucleus. Conclusively, Hif-1α and MAPK participate in HSC activation upon hypoxia.

/pdf/hypoxia-inducible-factor-1alpha-and-mapk-co-regulate-47ge79pei0.pdf

Hypoxia-Inducible Factor-1alpha and MAPK Co-Regulate Activation of Hepatic Stellate Cells upon Hypoxia Stimulation

The bacterial protein flagellin can trigger immune responses to infections by interacting with TLR5 on APCs, and Ag-flagellin fusion proteins can act as effective vaccines. We report that flagellin-related peptides containing a His-tag and sequence related to conserved N-motif (aa 85-111) of FliC flagellin, purportedly involved in the interaction of flagellin with TLR5, can be used to target delivery of liposomal Ag to APCs in vitro and in vivo. When engrafted onto liposomes, two flagellin-related peptides, denoted as 9Flg and 42Flg, promoted strong liposome binding to murine bone marrow-derived dendritic cells and CD11c(+) splenocytes, and cell binding correlated with expression of TLR5. Liposomes engrafted with 9Flg or 42Flg induced functional MyD88-dependent maturation of dendritic cells in vivo. The vaccination of mice with 9Flg liposomes containing OVA induced OVA-specific T cell priming, increased the number of Ag-responsive IFN-gamma-producing CD8(+) T cells, and increased Ag-specific IgG(1) and IgG(2b) in serum. Importantly, the vaccination of C57BL/6 mice with syngeneic B16-OVA-derived plasma membrane vesicles, engrafted with 9Flg or 42Flg, potently inhibited tumor growth/metastasis and induced complete tumor regression in the majority of mice challenged with the syngeneic B16-OVA melanoma, in the lung and s.c. tumor models. Strong antitumor responses were also seen in studies using the s.c. P815 tumor model. Therefore, vaccination with Ag-containing liposomes engrafted with 9Flg or 42Flg is a powerful strategy to exploit the innate and adaptive immune systems for the development of potent vaccines and cancer immunotherapies.

/pdf/antigen-containing-liposomes-engrafted-with-flagellin-1q84wr9r5g.pdf

Antigen-Containing Liposomes Engrafted with Flagellin-Related Peptides Are Effective Vaccines That Can Induce Potent Antitumor Immunity and Immunotherapeutic Effect

Aims: A hepatoma cell line, HepG2, was used as a model system to detect Toll-like receptor (TLR) expression in hepatocytes and examine the antiviral effect on hepatitis B virus (HBV).



Methods and Results:  Toll-like receptor expression was detected in HepG2 cells by RT-PCR. The TLRs, which were strongly expressed in HepG2 cells, were stimulated with specific ligands. Interferon (IFN) response was evaluated poststimulation with Western blotting for signal transduction and activators of transcription-1. Furthermore, HepG2 cells were transiently transfected with wild-type HBV 1·3-fold over-length plasmid and treated with specific ligands at indicated times. Replication of HBV DNA, transcription of HBV RNA intermediate and expression of HBV antigens were respectively detected by Southern blotting, real time PCR, ELISA and Western blotting. Activation of different TLRs induced antiviral effects on HBV to varying degrees.



Conclusions:  The TLRs, which were strongly expressed in HepG2 cells, could be stimulated with specific ligands. Activation of TLRs induced apparent production of antiviral cytokines such as IFN-α/β and inhibited HBV lifecycle in the hepatocyte cell model.



Significance and Impact of the Study:  Expression of TLRs in hepatocytes may be related to local immunity of liver and participate in the outcome of viral hepatitis.

https://sfamjournals.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2672.2008.03896.x

TLRs antiviral effect on hepatitis B virus in HepG2 cells.

Aims

This study aimed to investigate the ability of CpG7909 adjuvant to enhance immunogenicity and protective efficacy of a subunit vaccine composed of ESAT6-Ag85A fusion protein (Pe685a) of Mycobacterium tuberculosis.



Methods and Results

ELISA was used to detect specific antibody and IFN-γ expression in sera; ELISPOT, to detect IFN-γ expression in splenocytes; MTT assay and FACS, to detect T-lymphocytes proliferation in spleens; and RT-PCR, to detect cytokines expression in lungs of mice after immunization. Bacterial load and histopathological lesions in lungs or spleens of mice challenged with Myco. tuberculosis H37Rv strain were analysed. Compared with incomplete Freund's adjuvant, CpG7909 induced more potent production of Pe685a-specific IgG2a/IgG1 antibody and higher expression of IFN-γ in sera, stimulated more generation of antigen-specific IFN-γ-secreting splenocytes, enhanced frequencies of CD3+CD4+ and CD3+CD8+ T-lymphocytes in spleen and increased transcription of TNF-α, IFN-γ, IL-6 and TLR9 in lung. However, lower bacterial load in lung and less severe lung pathology were not observed in CpG7909 group mice.



Conclusions

CpG7909 is able to enhance immunological effects of Pe685a subunit vaccine, but does not confer significant protective efficacy against Myco. tuberculosis infection.



Significance and Impact of the Study

CpG7909 as an adjuvant of subunit vaccine against Myco. tuberculosis is worthy of further investigation.

CpG7909 adjuvant enhanced immunogenicity efficacy in mice immunized with ESAT6-Ag85A fusion protein, but does not confer significant protection against Mycobacterium tuberculosis infection.

Aims Gastric adenocarcinoma develops through a cascade of precancerous lesions. Determining surveillance intervals and timely reminding patients with precancerous lesions is critical but time-consuming. We aimed to create a system that automatically categorizes patients into different surveillance intervals and sends patients timely follow-up messages. 

Automatic identification of gastroscopy surveillance interval and follow-up reminder for high-risk patients undergoing screening upper endoscopy

Accurate assessment of early non-alcoholic fatty liver disease (NAFLD) is important to reduce the possible complications. The purpose of the present study was to develop a simple algorithm for the screening of NAFLD in the Chinese population based on routine anthropometric data and laboratory tests.This is a cross-sectional design.The subjects (1145) underwent routine physical examinations. The variables in the NAFLD index (NFI) were obtained by a stepwise multiple logistic regression analysis on 1000 bootstrap samples. The area under the receiver-operating characteristic (AUROC) was used to evaluate the accuracy of the NFI.Multivariate analysis showed that body mass index, fasting blood glucose, ratio of alanine aminotransferase to aspartate aminotransferase, and triglyceride were included in the final equation. The AUROC of the NFI was 0.919 (95% confidence interval = 0.901-0.937). An NFI of <31.0 excluded the possibility of NAFLD with a sensitivity of 96.9%, and at a value of >36.0, the NFI could detect NAFLD with a specificity of 98.9%.NFI was a cost-effective NAFLD-screening model, which had a high accuracy for predicting NAFLD at early stages in the Chinese population. 

NFI, a clinical scoring tool for predicting non-alcoholic fatty liver in the Chinese population

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Papers

TLRs antiviral effect on hepatitis B virus in HepG2 cells.

CpG7909 adjuvant enhanced immunogenicity efficacy in mice immunized with ESAT6-Ag85A fusion protein, but does not confer significant protection against Mycobacterium tuberculosis infection.

Automatic identification of gastroscopy surveillance interval and follow-up reminder for high-risk patients undergoing screening upper endoscopy

NFI, a clinical scoring tool for predicting non-alcoholic fatty liver in the Chinese population