Anti-CD95-induced lethality requires radioresistant Fcgamma RII+ cells. A novel mechanism for fulminant hepatic failure.
The Jo2 anti-mouse CD95 monoclonal antibody induces lethality in mice characterized by hepatocyte death and liver hemorrhage. Mice bearing a defect in Fas expression or in the Fas-mediated apoptotic pathway are resistant to Jo2. Here we show that FcgammaRII knockout mice or mice with monoclonal antibody-blocked FcgammaRII are also resistant to Jo2. The critical FcgammaRII(+) cells are radioresistant and could not be reconstituted with splenic cells. Death of sinusoidal lining cells and destruction of sinusoids were observed, consistent with the characteristic liver hemorrhage and the selective FcgammaRII expression in sinusoidal lining cells but not hepatocytes. Hemorrhage developed coincident with hepatocyte death and the sharp rise of serum alanine aminotransferase and alanine aminotransferase. Invariably, moribund mice showed severe liver hemorrhage and destruction of sinusoids. The data demonstrate a novel mechanism by which the destruction of liver sinusoids, induced by the Jo2-mediated co-engagement of Fas and FcgammaRII, leads to severe hemorrhage and lethal fulminant hepatitis.
Jodo
Satoshi
S
Arthritis Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Kung
John T
JT
Xiao
Sheng
S
Chan
Derek V
DV
Kobayashi
Seiichi
S
Tateno
Masatoshi
M
Lafyatis
Robert
R
Ju
Shyr-Te
ST
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis; D016923:Cell Death; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000528:radiation effects; D017093:Liver Failure / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000737:chemistry / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D008070:Lipopolysaccharides; D017452:Receptors, IgG; D019014:fas Receptor; D000410:Alanine Transaminase