Abnormal complement-mediated immune clearance in MRL-lpr/+ heterozygote mice: dose-dependent effect of the Fas antigen mutation.
We have previously demonstrated decreased complement-mediated clearance of IgG-opsonized erythrocytes in mice homozygous for the lpr mutation of the fas gene (BALB/c-lpr/lpr, C57BL/6-lpr/lpr, and MRL-lpr/lpr). To further test the hypothesis that the lpr mutation leads to a series of events resulting in selectively decreased complement-mediated immune clearance, in vivo clearance rate data were obtained from MRL-lpr/+F1, F2, and reciprocal backcross mice. Southern analysis of genomic DNA extracted from F2 and backcross mice was used to correlate the presence of the normal fas gene or the lpr mutation with normal or decreased complement-mediated clearance, respectively. Mean clearance rate constants for complement-dependent sequestration and phagocytosis were significantly decreased in the group of F1, F2, and backcross mice compared to control BALB/c mice (P < 0.0001). Data correlating clearance rate parameters from F2 and backcross mice with their respective genotype demonstrated a dose effect of the lpr mutation on abnormal complement-dependent sequestration and phagocytosis (r > 0.98), with heterozygote mice expressing mean values approximately half of those observed in +/+ homozygotes. These data demonstrate that the presence of the lpr mutation of the fas gene is strongly correlated in a dose-dependent manner with abnormal complement-mediated immune clearance. This clearance defect may be one mechanism through which the lpr mutation acts as an enhancer of autoimmune disease. Reduced clearance of immune complexes would increase the likelihood of tissue deposition and immune-mediated damage.
Meryhew
N L
NL
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Tam
P E
PE
Seim
J K
JK
Messner
R P
RP
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology*; D003433:Crosses, Genetic; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D006579:Heterozygote; D007700:Kinetics; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009895:Opsonin Proteins; D010587:Phagocytosis / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics*
D009895:Opsonin Proteins; D019014:fas Receptor; D003165:Complement System Proteins