PRODUCTION OF CONGENIC MOUSE STRAINS CARRYING GENOMIC INTERVALS CONTAINING SLE-SUSCEPTIBILITY GENES DERIVED FROM THE SLE-PRONE NZM2410 STRAIN

Systemic lupus erythematosus is inherited as a complex polygenic trait . Four genomic intervals containing major SLE-susceptibility loci were previously identified by interval mapping in the NZM2410 mouse model. In this paper, we utilized a marker-assisted selection protocol to pr oduce four congenic mouse strains, each carrying an NZM2410-derived SL E-susceptibility interval on a C57BL/6-resistant background. Each stra in carries only one susceptibility allele derived from this polygenic model and consequently can be used to characterize the specific compon ent phenotypes contributed by individual SLE-susceptibility genes. We illustrate the efficacy of this approach with phenotypic data for one of our congenic strains, B6.NZMH2(z). Our results indicate that this s ingle genomic interval from Chromosome (Chr) 17 of NZM2410 can mediate increased levels of IgG autoantibodies specific for chromatin and tha t, similar to results obtained in our original genetic cross, B6.NZMH2 (z/b) heterozygotes are more prone than B6.NZMH2(z) homozygotes to the development of humoral autoimmunity to nuclear antigens. These result s illustrate the feasibility of using congenic strains to dissect the complex pathogenic mechanisms that mediate polygenic SLE. These congen ic strains will be valuable tools in the genetic analysis of SLE susce ptibility. In future studies, these congenic strains will be interbred to produce bi- and tri-congenic strains in order to assess the role o f genetic interactions in the expression of specific components of SLE pathogenesis. They will also be instrumental to the positional clonin g and identification of the genes responsible for SLE susceptibility, via the production of congenic recombinants.