metallothionein and Hepatic-Encephalopathy

The molecular and cellular mechanisms responsible for cytotoxic T lymphocyte (CTL)-induced immunopathology are not well defined. Using a model in which hepatitis B surface antigen (HBsAg)-specific CTL cause an acute necroinflammatory liver disease in HBsAg transgenic mice, we demonstrate that class I-restricted disease pathogenesis is an orderly, multistep process that involves direct as well as indirect consequences of CTL activation. It begins (step 1) almost immediately as a direct antigen-specific CTL-target cell interaction that triggers the HBsAg-positive hepatocyte to undergo programmed cell death (apoptosis). It progresses (step 2) within hours to a focal inflammatory response in which antigen-nonspecific lymphocytes and neutrophils amplify the local cytopathic effect of the CTL. The most destructive pathogenetic function of the CTL, however, is to secrete interferon gamma when they encounter antigen in vivo, thereby activating the intrahepatic macrophage and inducing a delayed-type hypersensitivity response (step 3) that destroys the liver and kills the mouse. We propose that the principles illustrated in this study are generally applicable to other models of class I-restricted, CTL-induced immunopathology, and we suggest that they contribute to the immunopathogenesis of viral hepatitis during hepatitis B virus infection in humans.

Topics: Animals; CD3 Complex; CD4 Antigens; CD8 Antigens; Hepatic Encephalopathy; Hepatitis B Surface Antigens; Hepatitis B virus; Histocompatibility Antigens Class I; Immunoenzyme Techniques; Immunotherapy, Adoptive; Inflammation; Interferon-gamma; Liver; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Necrosis; Promoter Regions, Genetic; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Tumor Necrosis Factor-alpha

A patient who developed valproate-associated hepatotoxicity had significantly lower serum levels of total protein, albumin and selenium than the controls. This study shows that with the beginning of the hepatic coma metallothionein (MT) appeared in the serum mainly in the form of Zn-thionein, which altered the Zn distribution pattern of the serum in a characteristic manner. HPLC-ICP3 was successfully applied to the simultaneous speciation of elements and characterization of MT by the use of one gel permeation column.

Topics: Blood Proteins; Child; Chromatography, High Pressure Liquid; Copper; Epilepsy; Hepatic Encephalopathy; Humans; Metallothionein; Selenium; Serum Albumin; Valproic Acid; Zinc