Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis.
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.
Ando
K
K
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037.
Moriyama
T
T
Guidotti
L G
LG
Wirth
S
S
Schreiber
R D
RD
Schlicht
H J
HJ
Huang
S N
SN
Chisari
F V
FV
D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D006501:Hepatic Encephalopathy / Q000276:immunology* / Q000473:pathology*; D006514:Hepatitis B Surface Antigens / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology; D006515:Hepatitis B virus / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007124:Immunoenzyme Techniques; D016219:Immunotherapy, Adoptive; D007249:Inflammation; D007371:Interferon-gamma / Q000502:physiology; D008099:Liver / Q000276:immunology / Q000473:pathology*; D008297:Male; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009336:Necrosis; D011401:Promoter Regions, Genetic; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D006514:Hepatitis B Surface Antigens; D015395:Histocompatibility Antigens Class I; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008668:Metallothionein