Host modifier genes affect mouse autoimmunity induced by the lpr gene

Area of Science:

• Immunology
• Genetics
• Autoimmunity

Background:

• Defects in CD95-mediated apoptosis cause lymphoproliferation and autoimmunity in lpr mice.
• Disease severity in lpr mice is significantly modulated by host genetic factors.

Purpose of the Study:

• To identify and map host genes (Lprm) that modify the effects of the lpr gene.
• To understand the genetic basis of autoimmune manifestations in MRL/lpr mice.

Main Methods:

• Immunopathological and genetical analyses of 82 MRL/lpr x (MRL/lpr x C3H/lpr) F1 mice.
• Microsatellite analysis and quantitative trait locus (QTL) analysis to map modifier genes.
• Evaluation of vasculitis, glomerulonephritis, spleen weight, lymph node weight, and anti-dsDNA autoantibody titers.

Main Results:

• Two loci, Lprm1 (chromosome 4) and Lprm2 (chromosome 3), were identified as modifiers of vasculitis, with distinct sex-specific effects.
• A recessive MRL allele at Lprm3 (chromosome 14) suppressed glomerulonephritis.
• Recessive MRL alleles at Lprm4 (chromosome 5) and a locus on chromosome 16 (Lprm5) influenced spleen weight and anti-dsDNA autoantibody titers, respectively.
• Genotype combinations explained vasculitis severity and identified Lprm5 with a significant LOD score of 3.41 for autoantibody control.

Conclusions:

• Autoimmune disease manifestations in lpr mice are influenced by multiple, independently acting host modifier genes.
• These findings highlight the complex genetic architecture underlying autoimmune diseases.
• Candidate genes for Lprm loci were proposed based on map locations and comparison with known autoimmunity genes.