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 journalArticle

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

Fingerprint

Cytotoxic T-Lymphocytes
Transgenic Mice
Hepatitis
Hepatitis B Surface Antigens
Antigens
Delayed Hypersensitivity
Virus Diseases
Lymphocyte Activation
Hepatitis B virus
Cell Communication
Interferons
Liver Diseases
Hepatocytes
Neutrophils
Cell Death
Macrophages
Lymphocytes
Apoptosis
Liver

ASJC Scopus subject areas

  • Immunology

Cite this

Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. / Ando, K.; Moriyama, T.; Guidotti, L. G.; Wirth, S.; Schreiber, R. D.; Schlicht, H. J.; Huang, S. N.; Chisari, F. V.

In: Journal of Experimental Medicine, Vol. 178, No. 5, 1993, p. 1541-1554.

Research output: Contribution to journalArticle

Ando, K, Moriyama, T, Guidotti, LG, Wirth, S, Schreiber, RD, Schlicht, HJ, Huang, SN & Chisari, FV 1993, 'Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis', Journal of Experimental Medicine, vol. 178, no. 5, pp. 1541-1554. https://doi.org/10.1084/jem.178.5.1541
Ando, K. ; Moriyama, T. ; Guidotti, L. G. ; Wirth, S. ; Schreiber, R. D. ; Schlicht, H. J. ; Huang, S. N. ; Chisari, F. V. / Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. In: Journal of Experimental Medicine. 1993 ; Vol. 178, No. 5. pp. 1541-1554.
@article{3d903014afd54c16896f243b3c2fa455,
title = "Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis",
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.",
author = "K. Ando and T. Moriyama and Guidotti, {L. G.} and S. Wirth and Schreiber, {R. D.} and Schlicht, {H. J.} and Huang, {S. N.} and Chisari, {F. V.}",
year = "1993",
doi = "10.1084/jem.178.5.1541",
language = "English",
volume = "178",
pages = "1541--1554",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "5",

}

TY - JOUR

T1 - Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis

AU - Ando, K.

AU - Moriyama, T.

AU - Guidotti, L. G.

AU - Wirth, S.

AU - Schreiber, R. D.

AU - Schlicht, H. J.

AU - Huang, S. N.

AU - Chisari, F. V.

PY - 1993

Y1 - 1993

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0027453541&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027453541&partnerID=8YFLogxK

U2 - 10.1084/jem.178.5.1541

DO - 10.1084/jem.178.5.1541

M3 - Article

C2 - 8228807

AN - SCOPUS:0027453541

VL - 178

SP - 1541

EP - 1554

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 5

ER -