Ultrastructural localization of interferon-producing cells in the livers of patients with chronic hepatitis B

Dienes, Hans Peter; Heß, Georg; Wöorsdörfer, Marita; Rossol, S.; Gallati, H.; Ramadori, Giuliano; Büschenfelde, Karl‐Hermann Meyer zum

doi:10.1002/hep.1840130219

Cited by 11 publications

(13 citation statements)

References 20 publications

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“…36,[38][39][40] Our immunohistochemical analyses showed that TLR-3 and IFN-b localize primarily to portal tract macrophages and hepatocytes, whereas IFN-a was detected primarily in inflammatory cells (plasma cells, lymphocytes, macrophages) in the portal tract and in Kupffer cells. These data are consistent with previous studies of IFN-a localization in liver biopsies from patients with viral hepatitis, [41][42][43][44][45][46] in which Kupffer cells, lymphocytes and macrophages showed IFN-a positive staining. While hepatocytes have also been previously reported to express IFNa 41,[43][44][45] in chronic viral hepatitis, the expression of IFN-b in hepatocytes has not been demonstrated by Type I interferon in primary biliary cirrhosis Y Takii et al immunohistochemistry in vivo.…”

Section: Discussionsupporting

confidence: 93%

“…These data are consistent with previous studies of IFN-a localization in liver biopsies from patients with viral hepatitis, [41][42][43][44][45][46] in which Kupffer cells, lymphocytes and macrophages showed IFN-a positive staining. While hepatocytes have also been previously reported to express IFNa 41,[43][44][45] in chronic viral hepatitis, the expression of IFN-b in hepatocytes has not been demonstrated by Type I interferon in primary biliary cirrhosis Y Takii et al immunohistochemistry in vivo. Only a few report is available concerning the mRNA expression of IFN-b in hepatocytes in vivo or hepatocyte cell lines in vitro.…”

Section: Discussionsupporting

confidence: 93%

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Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

Takii

Nakamura

Ito

et al. 2005

Laboratory Investigation

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The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-a, -b, -c, interleukin (IL)-1b, -4, -6, -10, -12p40, -18, tumor necrosis factor-a) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-a, -b and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-a, -b) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-a is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-b and TLR-3. Furthermore, the level of IFN-a mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC. Laboratory Investigation (2005) 85, 908-920.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

Takii

Nakamura

Ito

et al. 2005

Laboratory Investigation

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“…Interferon (IFN) seems to be an important regulator of the local immune response in the liver of patients with chronic hepatitis B, because cells expressing IFN-a and -y are localized in the liver tissue of these patients (13 (C57BL/6 x DBA/2) mice were used to obtain fertilized eggs, and several hundred molecules of the SAP-IFN-y fragment (2.4 kb) were microinjected into the pronucleus of fertilized eggs, as described (19). When the mice were 4 weeks of age, total nucleic acid was extracted from a piece of the tail of each mouse and used for Southern blot analysis (20).…”

mentioning

confidence: 99%

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Toyonaga

Hino

Sugai

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

204

116

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Interferon-y may play an important role in the immune response and in inflammatory diseases, including chronic active hepatitis. To understand the role of interferon-y in the regulation of inflammation and to establish a mouse model of chronic active hepatitis, we produced transgenic mice in which the mouse interferon-y gene was regulated by a liver-specific promoter, the serum amyloid P component gene promoter. Four transgenic mouse lines were generated, and two of these lines expressed mRNA of interferon-y in the liver. Levels of serum transaminases increased gradually as a function of age and were significantly higher than those of interferon--negative littermates after 4 weeks after birth. One transgenic mouse line showed a histology of chronic active hepatitis similar to that found in human patients, although cirrhotic changes such as fibrosis were scarce. Thus, the liver-specific production of interferon-y is sufficient to induce chronic inflammatory disease and this mouse is a transgenic model of chronic active hepatitis.Chronic hepatic diseases, such as chronic active hepatitis and liver cirrhosis, are public health problems of worldwide importance and are major causes of mortality in certain areas of the world. Clinical and epidemiological studies (1-4) have clearly shown the importance of hepatitis B and C viruses (HBV, HCV) in chronic active hepatitis as well as hepatocellular carcinoma (HCC). Furthermore, studies ofpathology revealed that HCC arises in a cirrhotic liver and that chronic hepatitis is prerequisite for the development of HCC. The mechanisms responsible for HBV-or HCV-induced hepatocellular injury are not well understood. However, it is generally accepted that HBV is not directly cytopathic and that liver cell necrosis is dependent upon the host's immune response, directed at viral determinants on the hepatocyte membrane (5, 6). This immune response is mainly mediated by cytotoxic T lymphocytes (7).Several transgenic models of hepatic disease have been described. Chisari et al. (8) (10) showed that transgenic mice expressing the albumin-plasminogen activator gene develop progressive degenerative change in the liver due to accumulation ofRER-bounded multivesicular bodies. However, the principal lesion in these models appears to involve the hepatocyte secretory pathway and thus is different from that found in human patients.A model of acute hepatitis can be produced by administration of chemicals. However, remaining hepatocytes are induced to proliferate until the liver regains its original weight. Shull et al. (11) produced transforming growth factor (TGF)-,81-deficient mice. These mice developed an inflammatory liver disease similar to that found in HBV infection. However, about 20 days after birth these mice died due to a wasting syndrome. Mori et al. (12) demonstrated that liver changes histologically mimicking human hepatitis were produced in the mouse liver after repeated immunization with syngeneic crude liver proteins. However, it is not known whether hepatitis continues l...

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“…(31). However, their expression can be induced during HBV infection (32). Our results demonstrating recognition of endogenous HBV core antigen by proliferative CD4+, class 11-restricted T cells imply that HBV-infected hepatocytes may act as APC and activate CD4 + proliferative T cells in uzvo.…”

Section: Discussionmentioning

confidence: 69%

Proliferative and cytotoxic T-cell clones recognize endogenously synthesized HBcAG in an asymptomatic HBsAg carrier

et al. 1993

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The characterization of immune responses to hepatitis B virus is crucial for the understanding of hepatitis B virus-caused liver disease. However, lack of a suitable autologous effector-target cell system makes a precise study of the pathogenesis of hepatitis B difficult. In this study we established a model system by using autologous HBcAg-expressing Epstein-Barr virus-immortalized lymphoblastoid cell lines as stimulator/target cells. T-cell cultures were established by repetitive stimulation with recombinant HBcAg or autologous HBcAg-expressing lymphoblastoid cell lines. Both proliferative and cytotoxic T-cell clones were obtained from the peripheral blood of an asymptomatic HBsAg carrier. Clones T12 (CD8+) and T2B (CD4+) were cytotoxic clones specific against autologous lymphoblastoid cell lines expressing endogenously synthesized HBcAg, whereas five CD4+ T-cell clones proliferated in response to lymphoblastoid cell lines incubated with exogenous recombinant HBcAg and autologous HBcAg-expressing lymphoblastoid cell lines. These results indicate that autologous HBcAg-expressing lymphoblastoid cell lines are appropriate stimulator/target cells for the study of HBcAg-specific T lymphocytes. By using this approach, we have demonstrated that both proliferative and cytotoxic T lymphocytes recognizing endogenously synthesized HBcAg are induced during chronic hepatitis B virus infection.

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Ultrastructural localization of interferon-producing cells in the livers of patients with chronic hepatitis B

Cited by 11 publications

References 20 publications

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Proliferative and cytotoxic T-cell clones recognize endogenously synthesized HBcAG in an asymptomatic HBsAg carrier

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