Dysfunction of Immune Systems and Host Genetic Factors in Hepatitis C Virus Infection with Persistent Normal ALT

Patients with chronic hepatitis C (CHC) virus infection who have persistently normal alanine aminotransferase levels (PNALT) have mild inflammation and fibrosis in comparison to those with elevated ALT levels. The cellular immune responses to HCV are mainly responsible for viral clearance and the disease pathogenesis during infection. However, since the innate and adaptive immune systems are suppressed by various kinds of mechanisms in CHC patients, the immunopathogenesis of CHC patients with PNALT is still unclear. In this review, we summarize the representative reports about the immune suppression in CHC to better understand the immunopathogenesis of PNALT. Then, we summarize and speculate on the immunological aspects of PNALT including innate and adaptive immune systems and genetic polymorphisms of HLA and cytokines

Biological Significance of HCV in Various Kinds of Lymphoid Cells

It has been reported that HCV can infect not only hepatocytes but also various kinds of lymphoid cells. Although many reports have described the biological significance of lymphotropic HCV, the issue remains controversial since the target lymphoid cells might have various kinds of functions in the immune system. One of the important roles of lymphoid cells in HCV replication is being a reservoir of HCV. Several groups described the detection of HCV-RNA in lymphoid cells after HCV eradication in plasma. Another important role of lymphotropic HCV is that it acts as a carcinogenic agent and induces immune dysfunction. In this paper, we summarize the reports regarding the biological significance of lymphotropic HCV in representative lymphoid cells

PBC: Animal Models of Cholangiopathies and Possible Endogenous Viral Infections

Primary Biliary Cirrhosis (PBC) is considered an autoimmune disease characterized by immune-mediated destruction of the intrahepatic bile ducts and its characteristic serologic marker, the anti-mitochondrial antibody (AMA). Several factors were proposed to clarify the pathological and immunological mechanisms of PBC. Immunological reaction with a bacterial or a viral association was identified in the previous report, and it seems probable that PBC was thought to have such an etiology. The majority of patients with PBC was reported to have both RT-PCR and immunohistochemistry evidence of human betaretrovirus infection in lymph nodes or in 2008, the patient who developed PBC with high HIV viral load had an antiviral therapy and recovered. To understand the etiology of PBC associated with infection, several factors should be considered and especially animal models may be useful. In this paper, we introduce three typical animal models of PBC: the dominant-negative form of transforming growth factor-β receptor type II (dnTGFβRII) mouse, IL-2Rα−/− mouse and NOD.c3c4 mouse, are enumerated and described, and we discuss previous reports of viral infection associated with PBC and consider the etiology of PBC from our analysis of results in NOD.c3c4 mouse

Putrescine-dependent Tumor Invasion

Our previous study showed that treatment of highly invasive rat ascites hepatoma (LC-AH) cells with α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, decreased both their intracellular level of putrescine and their in vitro invasion of a monolayer of calf pulmonary arterial endothelial (CPAE) cells, and that both these decreases were completely reversed by exogenous putrescine, but not spermidine or spermine. Here we show that all adhering control (DFMO-untreated) cells migrated beneath CPAE monolayer with morphological change from round to cauliflower-shaped cells (migratory cells). DFMO treatment increased the number of cells that remained round without migration (nonmigratory cells). Exogenous putrescine, but not spermidine or spermine, induced transformation of all nonmigratory cells to migratory cells with a concomitant increase in their intracellular Ca2+ level, [Ca2+]i. The putrescine-induced increase in their [Ca2+]i preceded their transformation and these effects of putrescine were not affected by antagonists of the voltage-gated Ca2+ channel, but were completely suppressed by ryanodine, which also suppressed the invasiveness of the control cells. The DFMO-induced decreases in both [Ca2+]i and the invasiveness of the cells were restored by thapsigargin, which elevated [Ca2+]i by inhibiting endoplasmic Ca2+-ATPase, indicating that thapsigargin mimics the effects of putrescine. These results support the idea that putrescine is a cofactor for Ca2+ release through the Ca2+ channel in the endoplasmic reticulum that is inhibited by ryanodine, this release being initiated by cell adhesion and being a prerequisite for tumor cell invasion

Toll-Like Receptors Signaling Contributes to Immunopathogenesis of HBV Infection

Innate and adaptive immune systems have important role in the pathogenesis of acute and chronic infection with hepatitis B virus (HBV). These immune responses are mediated through complex interactions between the innate immune response and adaptive immune response. Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize the molecular patterns associated with microbial pathogens. So far, TLR1 to 13 were found in human or mice and investigated to detect the target molecules and the downstream mechanisms of these unique systems. Stimulation by their ligands initiates the activation of complex networks of intracellular signaling transduction and innate and adaptive immune-related cells (NK, NK-T, monocytes, dendritic cells, T cells, B cells, and Tregs, etc.). However, reports on such relationships between HBV and TLRs have been relatively rare in comparison to those on HCV and TLRs, but have recently been increasing. Thus, a review of TLRs involved in the pathogenesis of HBV infection may be needed toward better understanding of the immunopathogenesis of HBV infection

Enhanced intracellular retention of a hepatitis B virus strain associated with fulminant hepatitis

AbstractA plasmid carrying 1.3-fold HBV genome was constructed from a HBV strain that caused five consecutive cases of fulminant hepatitis (pBFH2), and HepG2 cells were transfected with pBFH2 or its variants. The pBFH2 construct with A1762T/G1764A, G1862T, and G1896A showed the largest amount of core particle-associated intracellular HBV DNA, but no significant increase of extracellular HBV DNA in comparison with the wild construct, suggesting that these mutations might work together for retention of the replicative intermediates in the cells. The retention might relate to the localization of hepatitis B core antigen (HBcAg) in the nucleus of HepG2, which was observed by confocal fluorescence microscopy. HBcAg immunohistochemical examination of liver tissue samples obtained from the consecutive fulminant hepatitis patients showed stronger staining in the nucleus than acute hepatitis patients. In conclusion, the fulminant HBV strain caused retention of the core particles and the core particle-associated HBV DNA in the cells

Cholangiopathy: Genetics, Mechanism, and Pathology

Cholangiopathy is pathologically and pathogenetically heterogeneous and presents a broad spectrum of clinical manifestations. A majority of them are known for many years, while some are newly emerging diseases. Recent advances in biology and medicine have introduced new technologies to study the cholangiocyte biologies and physiologies and the genetics, and the pathogenesis and pathology of cholangiopathy is now being evaluated from the aspects of experimental and clinical studies. Several animal models have been developed for autoimmune and genetic cholangiopathy such as primary biliary cirrhosis and polycystic disease of the liver and biliary tract. Knowledge and understanding of these conditions have led to the development of promising therapies and novel tools to characterize these clinical conditions

Plasma L-Cystine/L-Glutamate Imbalance Increases Tumor Necrosis Factor-Alpha from CD14+ Circulating Monocytes in Patients with Advanced Cirrhosis

BACKGROUND AND AIMS: The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys) and secrete substantial amounts of L-Glutamate (L-Glu) via the transport system Xc- (4F2hc+xCT), and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes. METHODS: We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM), and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha. RESULTS: The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19), the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio. CONCLUSIONS: A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis

Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms

Although large cholangiocytes exert their functions by activation of cyclic adenosine 3',5'-monophosphate (cAMP), Ca(2+)-dependent signaling regulates the function of small cholangiocytes. Histamine interacts with four receptors, H1-H4HRs. H1HR acts by Gαq activating IP(3)/Ca(2+), whereas H2HR activates Gα(s) stimulating cAMP. We hypothesize that histamine increases biliary growth by activating H1HR on small and H2HR on large cholangiocytes. The expression of H1-H4HRs was evaluated in liver sections, isolated and cultured (normal rat intrahepatic cholangiocyte culture (NRIC)) cholangiocytes. In vivo, normal rats were treated with histamine or H1-H4HR agonists for 1 week. We evaluated: (1) intrahepatic bile duct mass (IBDM); (2) the effects of histamine, H1HR or H2HR agonists on NRIC proliferation, IP(3) and cAMP levels and PKCα and protein kinase A (PKA) phosphorylation; and (3) PKCα silencing on H1HR-stimulated NRIC proliferation. Small and large cholangiocytes express H1-H4HRs. Histamine and the H1HR agonist increased small IBDM, whereas histamine and the H2HR agonist increased large IBDM. H1HR agonists stimulated IP(3) levels, as well as PKCα phosphorylation and NRIC proliferation, whereas H2HR agonists increased cAMP levels, as well as PKA phosphorylation and NRIC proliferation. The H1HR agonist did not increase proliferation in PKCα siRNA-transfected NRICs. The activation of differential signaling mechanisms targeting small and large cholangiocytes is important for repopulation of the biliary epithelium during pathologies affecting different-sized bile ducts