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Dissection of BXSB lupus phenotype using mice congenic for chromosome 1 demonstrates that separate intervals direct different aspects of disease

Haywood, M. E.
Rogers, N. J.
Rose, S. J.
Boyle, Joseph
McDermott, Aileen
Rankin, J. M.
Thiruudaian, Vasuky
Lewis, Margarita
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Published in Journal of Immunology. 2004, vol. 173, no. 7, p. 4277-4285
Abstract To dissect the individual effects of the four non-MHC, autosomal loci (Bxs1 to Bxs4) that contribute to SLE susceptibility in BXSB mice, we generated congenic lines from chromosome 1 on a C57BL/10.Y(BXSB) (B10.Yaa) background for the intervals (values in megabases (Mb)) Bxs1 (46.3-89.2 Mb), Bxs1/4 (20.0-65.9 Mb), Bxs1/2 (64.4-159.0 Mb), and Bxs2/3 (105.4-189.0 Mb). Glomerulonephritis, qualitatively similar to that seen in the parental BXSB strain, developed in three of these congenic strains. Early onset, severe disease was observed in B10.Yaa.BXSB-Bxs2/3 congenic mice and caused 50% mortality by 12 mo. In B10.Yaa.BXSB-Bxs1/4 mice disease progressed more slowly, resulting in 13% mortality at 12 mo. The progression of renal disease in both of these strains was correlated with the level of anti-dsDNA Abs. B10.Yaa.BXSB-Bxs1 mice, despite their genetic similarity to B10.Yaa.BXSB-Bxs1/4 mice, developed a low-grade glomerulonephritis in the absence of anti-dsDNA Abs. Thus, Bxs4 directed an increase in titer and spectrum of autoantibodies, whereas Bxs1 promoted the development of nephritis. The Bxs2 interval was linked to the production of anti-dsDNA Abs without concomitant glomerulonephritis. In contrast, the Bxs3 interval was sufficient to generate classic lupus nephritis in a nonautoimmune-prone strain. Immune phenotype differed between controls and congenics with a significant increase in B220(+) cells in BXSB and B10.Yaa.BXSB-Bxs2/3, and an increase in CD4 to CD8 ratio in both BXSB and B10.Yaa.BXSB-Bxs1/4. Disease in the Bxs3 mice was delayed in comparison to the BXSB parental strain, emphasizing the necessity for multiple interactions in the production of the full BXSB phenotype.
Keywords AnimalsAutoantibodies/biosynthesis*Chromosome MappingCrosses, GeneticFemaleGenetic Markers/immunology*Genetic Predisposition to DiseaseImmunophenotypingLinkage (Genetics)Lupus Erythematosus, Systemic/*genetics/*immunology/mortalityLupus Nephritis/genetics/immunologyMaleMiceMice, CongenicMice, Inbred C57BLMice, Inbred Strains*PhenotypeSeverity of Illness IndexSplenomegaly/genetics/immunology
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PMID: 15383556
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