T Helper 17 Cells in Autoimmune Liver Diseases

Many autoimmune diseases are driven by self-reactive T helper (Th) cells. A new population of effector CD4+ T cells characterized by the secretion of interleukin (IL)-17, referred to as Th17 cells, has been demonstrated to be phenotypically, functionally, and developmentally distinct from Th1 and Th2 cells. Because the liver is known to be an important source of transforming growth factor-β and IL-6, which are cytokines that are crucial for Th17 differentiation, it is very likely that Th17 cells contribute to liver inflammation and autoimmunity. In contrast, another distinct subset of T cells, regulatory T cells (Treg), downregulate immune responses and play an important role in maintaining self-tolerance. In addition, there is a reciprocal relationship between Th17 cells and Tregs, in development and effector functions, and the balance between Th17 and Treg cells can affect the outcome of immune responses, particularly in autoimmune diseases. In this review, we will focus on the latest investigative findings related to Th17 cells in autoimmune liver disease

Uric acid is an independent risk factor for carotid atherosclerosis in a Japanese elderly population without metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>Carotid intima-media thickness (IMT) is an useful surrogate marker of cardiovascular disease. Associations between uric acid (UA), metabolic syndrome (MetS) and carotid IMT have been reported, but findings regarding the relationship have been inconsistent.</p> <p>Methods</p> <p>A total of 1,579 Japanese elderly subjects aged ≥65 years {663 men aged, 78 ± 8 (mean ± standard deviation) years and 916 women aged 79 ± 8 years} were divided into 4 groups according to UA quartiles. We first investigated the association between UA concentrations and confounding factors including MetS; then, we assessed whether there is an independent association of UA with carotid IMT and atherosclerosis in participants subdivided according to gender and MetS status.</p> <p>Results</p> <p>Carotid IMT was significantly increased according to the quartiles of UA in both genders without MetS and women with MetS. Multivariate logistic regression analysis showed that odds ratio (OR) {95% confidence interval (CI)} in men for carotid atherosclerosis was significantly increased in the third (OR, 1.75; 95% CI, 1.02-3.02), and fourth quartiles (OR, 2.01; 95% CI, 1.12-3.60) of UA compared with that in the first quartile of UA, and the OR in women was significantly increased in the fourth quartile (OR, 2.10; 95% CI, 1.30-3.39). Similarly, the ORs were significantly associated with increasing quartiles of UA in both genders without MetS, but not necessarily increased in those with MetS.</p> <p>Conclusions</p> <p>UA was found to be an independent risk factor for incidence of carotid atherosclerosis in both genders without MetS.</p

Unc93B1 Restricts Systemic Lethal Inflammation by Orchestrating Toll-like Receptor 7 and 9 Trafficking

SummaryToll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4+ T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking

Protein Kinase R Modulates c-Fos and c-Jun Signaling to Promote Proliferation of Hepatocellular Carcinoma with Hepatitis C Virus Infection

Double-stranded RNA-activated protein kinase R (PKR) is known to be upregulated by hepatitis C virus (HCV) and overexpressed in hepatocellular carcinoma (HCC). However, the precise roles of PKR in HCC with HCV infection remain unclear. Two HCV replicating cell lines (JFH-1 and H77s), generated by transfection of Huh7.5.1 cells, were used for experiments reported here. PKR expression was modulated with siRNA and a PKR expression plasmid, and cancer-related genes were assessed by real-time PCR and Western blotting; cell lines were further analyzed using a proliferation assay. Modulation of genes by PKR was also assessed in 34 human HCC specimens. Parallel changes in c-Fos and c-Jun gene expression with PKR were observed. Levels of phosphorylated c-Fos and c-Jun were upregulated by an increase of PKR, and were related to levels of phosphorylated JNK1 and Erk1/2. DNA binding activities of c-Fos and c-Jun also correlated with PKR expression, and cell proliferation was dependent on PKR-modulated c-Fos and c-Jun expression. Coordinate expression of c-Jun and PKR was confirmed in human HCC specimens with HCV infection. PKR upregulated c-Fos and c-Jun activities through activation of Erk1/2 and JNK1, respectively. These modulations resulted in HCC cell proliferation with HCV infection. These findings suggest that PKR-related proliferation pathways could be an attractive therapeutic target

On dendritic cell-based therapy for cancers

Dendritic cells (DCs), the most prevalent antigen-presenting cell in vivo, had been widely characterized in the last three decades. DCs are present in almost all tissues of the body and play cardinal roles in recognition of microbial agents, autoantigens, allergens and alloantigen. DCs process the microbial agents or their antigens and migrate to lymphoid tissues to present the antigenic peptide to lymphocytes. This leads to activation of antigen-specific lymphocytes. Initially, it was assumed that DCs are principally involved in the induction and maintenance of adaptive immune responses, but now it is evident that DCs also have important roles in innate immunity. These features make DCs very good candidates for therapy against various pathological conditions including malignancies. Initially, DC-based therapy was used in animal models of cancers. Data from these studies inspired considerable optimism and DC-based therapies was started in human cancers 8 years ago. In general, DC-based therapy has been found to be safe in patients with cancers, although few controlled trials have been conducted in this regard. Because the fundamentals principles of human cancers and animal models of cancers are different, the therapeutic efficacy of the ongoing regime of DC-based therapy in cancer patients is not satisfactory. In this review, we covered the various aspects that should be considered for developing better regime of DC-based therapy for human cancers

Hepatitis B virus (HBV)-transgenic mice as an investigative tool to study immunopathology during HBV infection

An overview is given regarding the use of hepatitis B virus (HBV) transgenic mice as an animal model of the HBV-carrier state. Initially, we show how HBV-transgenic mice have contributed insights into the immunopathobiological processes during HBV infection and later, we show how this new information from the experiments with HBV-transgenic mice could be used to develop new methods to combat HBV infection

Autoimmune hepatitis showing spontaneous remission and acute exacerbation

ABSTRACTAutoimmune hepatitis (AIH) represents a chronic liver disease with a progressive nature. Cortocosteroid therapy is routinely used to control this pathological condition. Herein, we describe a case of AIH with spontaneous remission and exacerbation. A previously healthy young Japanese woman presented with features of acute hepatitis. The patient was not acutely infected with hepatotrophic viruses and the possibility of drug-induced AIH was also excluded. A diagnosis of AIH was made from subjective symptoms and laboratory data, which showed increased levels of liver enzymes, total bilirubin, IgG and positive titers of antinuclear antibody. Finally, liver biopsy revealed an expansion of portal tracts and infiltration of mononuclear cells, including plasma cells. This patient experienced a total of three episodes of acute exacerbation of AIH during the past 5 years, two of which subsided spontaneously. An immunosuppressive drug was used to control the last episode of acute exacerbation of AIH, which was very similar to acute hepatitis. The immunosuppressive drug was withdrawn 7 months after the last epoisode of acute exacerbation of AIH and the patient is now passing an uneventful course. There are cases of spontaneous remission and acute exacerbation of AIH, although the underlying mechanism of this pathological process is yet to be determined. Liver biopsy is needed to diagnose these cases. Periodic follow up of these patients is required for proper management