Genetic complementation in female (BXSB x NZW)F2 mice

Area of Science:

• Genetics
• Immunology
• Autoimmune Diseases

Background:

• New Zealand Black (NZB), New Zealand White (NZW), and BXSB strains are lupus-prone.
• Hybrid crosses of these strains develop accelerated autoimmunity.
• The Y chromosome accelerator of autoimmunity (Yaa) influences lupus in males.

Purpose of the Study:

• Identify BXSB susceptibility loci without the Yaa.
• Investigate the genetic complementation of lupus susceptibility.
• Map quantitative trait loci (QTL) in female (BXSB x NZW)F(2) mice.

Main Methods:

• Genome-wide quantitative trait locus (QTL) mapping.
• Analysis of female (BXSB x NZW)F(2) mice.
• Phenotypic assessment including survival, autoantibodies, glomerulonephritis, and splenomegaly.

Main Results:

• Six QTL were identified on chromosomes 1, 4, 5, 6, 7, and 17.
• Survival mapped to chromosomes 5 and 17.
• Anti-chromatin antibodies mapped to chromosomes 4 and 17.
• Glomerulonephritis mapped to chromosomes 6 and 17.
• Splenomegaly mapped to chromosomes 1, 7, and 17.
• New QTL, Lxw1 and Lxw2, were designated on chromosomes 4 and 6.
• Non-MHC QTL on chromosomes 1 and 4 were BXSB-derived; others were NZW-derived.
• Few previously defined male-specific BXSB QTL were implicated, suggesting Yaa-dependency.

Conclusions:

• BXSB and NZB backgrounds contribute distinct genetic factors to lupus when combined with NZW.
• Some BXSB QTL may require the Yaa for expression.
• Understanding genetic complementation is crucial for defining lupus pathogenesis.