Immunological and pathological consequences of mutations in both Fas and Fas ligand.
The lpr mutation in mice results in premature termination of transcription of the gene encoding the apoptosis-signaling receptor Fas. As a result, lpr mice develop severe lymphoproliferation and lupus-like autoantibodies. Growing evidence suggests that the lpr mutation is "leaky" and that low levels of Fas are expressed in lpr mice. To determine if Fas expressed in lpr mice is contributing to apoptosis we generated a novel strain of mice (B6/lprgld) which is homozygous for both the lpr mutation and the gld mutation which encodes nonfunctional Fas ligand (FasL) protein. If low levels of Fas in B6/lpr mice contribute to apoptosis and lessen the severity of disease, the B6/lprgld mice, which also lack functional FasL, would be expected to develop a more severe form of disease than B6/lpr mice. Our results revealed no significant increase in either lymphoproliferation or autoimmunity in B6/lprgld mice compared to B6/lpr or B6/gld mice. Additionally, no increase in surface expression of Fas was detected by flow cytometry on B6/lprgld lymphocytes compared to B6/lpr lymphocytes. However, histological examination of B6/lprgld liver revealed a marked increase in lymphocytic infiltration, compared to livers of B6/lpr and B6/gld mice. Our results suggest that, while low levels of Fas in lpr mice may not be contributing to amelioration of lymphoproliferation or autoimmunity, they may be partially protecting the liver from abnormalities which arise in the absence of Fas-mediated apoptosis.
Weintraub
J P
JP
Department of Medicine, University of North Carolina, Chapel Hill 27599-7280, USA.
Godfrey
V
V
Wolthusen
P A
PA
Cheek
R L
RL
Eisenberg
R A
RA
Cohen
P L
PL
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003433:Crosses, Genetic; D053222:Fas Ligand Protein; D005260:Female; D005838:Genotype; D008099:Liver / Q000276:immunology / Q000473:pathology; D008206:Lymphatic Diseases / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009154:Mutation; D016133:Polymerase Chain Reaction; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology
D001323:Autoantibodies; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor