Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis

K. Ando, T. Moriyama, L. G. Guidotti, S. Wirth, R. D. Schreiber, H. J. Schlicht, S. N. Huang, F. V. Chisari

Research output: Contribution to journalArticlepeer-review

Abstract

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 γ 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.

Original languageEnglish
Pages (from-to)1541-1554
Number of pages14
JournalJournal of Experimental Medicine
Volume178
Issue number5
DOIs
Publication statusPublished - 1993

ASJC Scopus subject areas

  • Immunology

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