The investigators propose to characterize the immunogenetic basis of susceptibility to systemic lupus erythematosus in New Zealand Mixed (NZM)stain 2410. NZM 2410 is one of a collection of 27 NZN inbred mouse strains produced from an intercross of NZW and NZB. The genomes of the various NZM strains contain a mixture of alleles derived from NZW and NZB and exhibit varying levels of susceptibility to the spontaneous development of SLE. NZM strain 2410 mice develop acute SLE by the age of 10 months in both sexes.The investigators propose to analyze the inheritance of SLE susceptibility in NZM 2410 and to characterize the immunologic properties of the genes responsible. Specifically, the investigators will: 1) Identify genomic segments containing loci affecting susceptibility to SLE in NZM 2410. They have already identified genomic segments on chromosomes 4 and 7 that contain recessive loci affecting SLE susceptibility in a cross with C57BL/6. The investigators will complete this analysis and assess the correlation of inheritance of SLE susceptibility with a variety of SLE-associated traits including autoantibodies against ds DNA, histones, and retroviral gp70. 2) Produce congenic strains carrying NZM 2410-derived SLE susceptibility alleles on a C57BL/6 background. A collection of congenic strains carrying NZM 24 10-derived genomic segments containing SLE susceptibility alleles will be produced using a methodology that will allow completion of these lines within 2 years. 3) Reconstruct SLE susceptibility with poly congenic strains and assess the role of each SLE susceptibility locus in the pathogenesis of SLE. The investigators will intercross the congenic strains to produce bi and tri-congenic strains in various combinations in order to reconstruct SLE susceptibility and to assess the contribution of each SLE susceptibility locus, separately and in combination with other susceptibility loci, to the pathogenesis of SLE. 4) Fine map each SLE susceptibility locus using congenic recombinants and determine their origin and distribution among the NZN stains. Congenic recombinants will be produced and used to localize the positions of each SLE susceptibility locus into narrow intervals (approximately 5 cM). The strain origin (NZW or NZB) of these intervals will be determined and used to establish the strain origin of each SLE susceptibility allele.
