A familial case of autoimmune hepatitis.

Autoimmune hepatitis is a chronic liver disease, and both genetic background and environmental factors are related to its pathogenesis. Here, we report that out of five members of a family with similar human leukocyte antigen haplotypes, two developed autoimmune hepatitis, one was positive for antinuclear antibody, and the remaining two had no features of autoimmunity. The two patients with autoimmune hepatitis had a history of medication use, whereas the other family members did not. Our familial study suggests that in addition to genetic background, medication use and other environmental factors may be related to the onset of autoimmune hepatitis.

Protective role of interleukin-10-producing regulatory dendritic cells against murine autoimmune gastritis.

BACKGROUND: Regulatory dendritic cells (Reg-DCs), which induce regulatory T cells and interleukin (IL)-10 in vitro, are capable of inducing immunogenic tolerance in vivo. In this study, we assessed whether Reg-DCs modulate the course of autoimmune processes in a murine model of autoimmune gastritis (AIG). METHODS: AIG mice were produced by neonatal thymectomy of 3-day old BALB/c mice followed by administration of polyinosinic:polycytidylic acid (poly I:C). Reg-DCs were produced by culturing bone marrow DCs with IL-10, lipopolysaccharide, and parietal cell (PC) antigen for 2 days. In the course of development of AIG, BALB/c mice were administered either Reg-DCs, mature DCs, or phosphate-buffered saline, intraperitoneally, four times. The levels of gastritis and autoantibody to PC antigen were assessed serially in these mice. RESULTS: The stages of gastritis and the titers of autoantibody to PC antigen were significantly lower in Reg-DC-treated mice than in mature DC-treated mice (P<0.05). Spleen cells from Reg-DC-treated mice produced increased levels of IL-10 and decreased levels of IL-12p70 and interferon-gamma (P<0.05). Also, frequencies of IL-10-producing CD4(+)CD25(+) T cells in the spleen and Foxp3(+)CD4(+)CD25(+) T cells in the peripheral blood were significantly higher in Reg-DC-treated mice than in mature DC-treated mice (P<0.05). CONCLUSIONS: Taken together, these results suggest that increased induction of CD4(+)CD25(+) regulatory T cells by Reg-DCs might contribute to downregulation of inflammatory processes and autoantibody production during AIG development in mice.

Engineering immune therapy against hepatitis B virus.

Approximately 350-400 million people worldwide are chronically infected with the hepatitis B virus (HBV). These individuals harbor the virus for their whole life and they transmit the virus to uninfected individuals. In addition, considerable numbers of chronic HBV carriers develop progressive liver diseases like chronic hepatitis B, liver cirrhosis and hepatocellular carcinoma. At present, antiviral agents like type-1 interferons, lamivudine, adefovir and entacavir are used to treat a selected population of chronic HBV carriers. These antiviral treatments are not satisfactory in that they are unable to eradicate HBV, only partially efficient in less than 30% subjects, expensive, can have debilitating side-effects and require constant monitoring. In addition, once treatment is stopped, the virus and clinical conditions return in many patients. Recent advancements in cellular and molecular biology indicate that the host's immune responses to HBV play cardinal roles during acquisition, pathogenesis, progression, and complications of chronic HBV infection. Immune responses are also important in the context of antiviraltherapy and clinical recovery. This explains why the efficacy of antiviral drugs is limited even in some selected patients with chronic HBV infection. Various published work now state that HBV-specific immunity may be beneficial for patients with chronic HBV infection and non-HBV-specific immunity may be related to flare up of liver diseases. Accordingly, a new few field of immunological research and clinical application of prophylactic vaccines (vaccine therapy) has been started in chronic HBV carriers. Vaccine therapy has inspired optimism as a new therapeutic approach, but it is unlikely that the present regimen of vaccine therapy will stand the test of time. Based on present understandings about vaccine/host interactions, we provide herein an outline for engineering more potent regimen of HBV-specific immune therapy against HBV.

Co-infection with hepatitis B virus genotype D and other genotypes in Western Japan.

OBJECTIVE: Genotypes B and C are the prevalent hepatitis B virus (HBV) genotypes in eastern Asia. Although very rare in this region of the world, genotype D was found to be prevalent in a small area of western Japan. In this study, we confirm the frequency and clinical significance of co-infection with different genotypes among patients from that area infected with genotype D. METHODS: Twenty-three patients from the same area of western Japan infected with HBV genotype D, determined using a genotyping enzyme immunoassay, were studied. Cloning was done using DNA extracted from serum samples, and polymerase chain reaction assays with the restriction fragment length polymorphism for HBV genotyping were performed with 10 clones from each patient. RESULTS: Four (17.4%) of the 23 patients were found to be co-infected with HBV genotype C, and the HB surface antigen subtype was ayw in both mono- and co-infected patients. No clinical differences were found between mono-infected and co-infected patients carrying genotype D. CONCLUSION: A significant number of patients from the study area found to be infected with HBV genotype D were co-infected with genotype C. Additional study with a larger number of patients is needed to elucidate the possible clinical significance.

Glycyrrhizin enhances interleukin-10 production by liver dendritic cells in mice with hepatitis.

BACKGROUND: Glycyrrhizin (GL), an aqueous extract of licorice root, is known to have various immune-modulating and biological response-modifier activities. GL is used in patients with hepatitis to reduce the activity of liver inflammation; however, the mechanism underlying the anti-inflammatory activity of GL is poorly understood. As antigen-presenting dendritic cells (DC) in the tissue play a major role in the regulation of the inflammatory mucosal milieu during tissue inflammation, we studied whether the function of liver DC was altered by GL therapy in a murine model of concanavalin-A (con A)-induced hepatitis. METHODS: Liver DC were propagated from control mice or mice with Con-A-induced hepatitis, and the effect of GL on liver DC was evaluated in vivo and in vitro. RESULTS: The levels of interleukin (IL)-10 produced by liver DC were significantly lower in mice with Con-A-induced hepatitis compared with control mice. However, treatment with GL caused increased production of IL-10 in mice with Con A-induced hepatitis. The increased production of IL-10 by mice with Con A-induced hepatitis was also confirmed in vitro by culturing liver DC with GL. CONCLUSIONS: This study indicates that increased production of IL-10 by liver DC due to GL administration may be involved in downregulation of the levels of liver inflammation in mice with Con A-induced hepatitis. Glycyrrhizin (GL), an aqueous extract of licorice root, is known to have various immune-modulating and biological response-modifier activities. GL is used in patients with hepatitis to reduce the activity of liver inflammation; however, the mechanism underlying the anti-inflammatory activity of GL is poorly understood. As antigen-presenting dendritic cells (DC) in the tissue play a major role in the regulation of the inflammatory mucosal milieu during tissue inflammation, we studied whether the function of liver DC was altered by GL therapy in a murine model of concanavalin-A (Con A)-induced hepatitis.

Defective antigen-presenting capacity of murine dendritic cells during starvation.

Significant impairments of several aspects of immunity have been described in acute and chronic nutritional deficiencies; however, there have been few studies on antigen-presenting cells during starvation. We examined the antigen-presenting capacities of mouse dendritic cells (DCs) from lymphoid organ (spleen DCs) and non-lymphoid tissue (liver DCs) during starvation. The total numbers of spleen DCs and liver DCs were significantly fewer in starved mice than in control mice. Functional analysis showed that the proliferative activities of spleen DCs and liver DCs were significantly impaired in starved mice compared with control mice. In particular, liver DCs from starved mice were unable to induce interferon-gamma. Liver DCs from starved mice were unable to induce proliferation of antigen-specific memory lymphocytes. These data indicated that one major cause of impairment of immunologic responses during starvation may be mediated through DCs.