Increased susceptibility of fas mutant MRL-lpr/lpr mice to staphylococcal enterotoxin B-induced septic shock.
MRL-lpr/lpr mice are defective in the fas Ag/APO-1 apoptosis gene (CD95). Using the hepatotoxin D-galactosamine (D-GalNH2), we demonstrate that MRL-lpr/lpr mice have an increased susceptibility to staphylococcal enterotoxin B (SEB)-induced lethal shock, which causes them to exhibit the septic shock-like behaviors of fur ruffling and listlessness, and death occurs within 8 to 18 h. SEB susceptibility is greater in V beta 8.2 TCR transgenic MRL-lpr/lpr mice than in nontransgenic mice. In studies designed to elucidate the molecular pathways of SEB-induced septic shock, we found that C57Bl/6.Ab0/Ab0, MHC class II-deficient "C2D" mice, but not C57Bl/6-(+/+) mice, are nonresponsive to challenge with SEB. C2D mice, backcrossed with the fas mutation resulting in double-knockout C2D;lpr/lpr mice, are more susceptible to challenge with SEB/D-GalNH2. The LD50s for C57Bl/6.C3H-gld/gld "fas ligand-mutant mice" challenged with SEB/D-GalNH2 were comparable to C57Bl/6.MRL-lpr/lpr and MRL-lpr/lpr mice, suggesting that reciprocal mutations in either fas or fas ligand increases susceptibility to bacterial superantigens (SAGs). SEB-induced lethal shock can be reversed by treatment with Abs to V beta 8 TCR, MHC class II Ia+, IL-2, and TNF-alpha, by the immunosuppressant cyclosporin A, or by treatment with carbocyclic nucleoside analogues. These data indicate that SAG-induced septic shock is dependent on interactions with the TCR and MHC class II Ags, and they also suggest a critical role for a functional fas and/or fas ligand in resistance to SAG-induced septic shock.
Mountz
J D
JD
Department of Medicine, University of Alabama at Birmingham, USA.
Baker
T J
TJ
Borcherding
D R
DR
Bluethmann
H
H
Zhou
T
T
Edwards
C K
CK
D000818:Animals; D004768:Enterotoxins / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D012772:Shock, Septic / Q000276:immunology*; D013210:Staphylococcus; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology
D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D019014:fas Receptor