We have discovered that a complex series of epistatic interactions between Sle1, Sle3, and Sle6 mediate a devastating autoimmune pathology in (B6.NZMcl X NSW)FI hybrids. Our analysis thus far indicates: 1) that fatal autoimmune nephritis in this model is completely dependent upon a recessive epistatic interaction between a gene in the Sle1 genomic interval and Sle3 and Sle6; 2) that Sle1, Sle3, Sle5, and Sle6 fail to produce autoimmune disease in NZW due to the presence of two suppressive modifiers in the NZW genome, which we have designated Sol1 and Sol2; and 3) that Sol1 and Sol2 are recessive and are located in genomic intervals on chromosomes 9 and 17, respectively. We now propose to characterize these epistatic interactions in detail and identify the genetic pathways to lupus susceptibility that are inhibited by Sol1 and Sol2. We have 4 specific aims: 1) To fine map the position of the epistatic susceptibility locus within the Sle1 interval. As a component of another project, we have produced an extensive panel of congenic recombinant progeny that have mapped Sle1 into a 0.5 cM interval on chromosome 1. We will use this panel of B6.NZMc1 recombinants to fine map the position of the epistatic susceptibility locus and determine whether it co-localizes with Sle1. 2) To produce interval-specific B6 congenic strains carrying Sle6 and Sol1 and characterize their epistatic properties. We will use marker assisted selection protocols to rapidly produce B6 congenic strains carrying Sle6, Sol1, and Sol2. Their component phenotypes will be assessed and their epistatic interactions with Sle1, Sle3, and Sle5 will be determined via analysis of bi- and tri-congenic strains. These experiments will determine which genetic pathways to lupus susceptibility are suppressed by Sol1 and Sol2 and will determine which pathway is effected by Sle6. 3) To fine map Sol1 and Sol2 using congenic recombinants. Fine mapping of Sol1 and Sol2 will be performed via the generation and analysis of congenic recombinants. Our goal will be to localize these genes to less than 1.0 cM intervals and evaluate key candidate genes within the intervals. 4) To screen for epistatic modifiers interacting with Sle5 and Sle3. We will cross B6.NZMc7 and the two sub-intervals B6.NZMc7c and B6.NZMc71 with NZW and monitor the development of autoimmune phenotypes. This analysis will determine whether either of these susceptibility loci can activate other autoimmune loci in manner similar to Sle1. Our long-term goal will be to delineate the genetic pathways responsible for lupus pathogenesis and identify the genes that both enhance and suppress susceptibility to SLE.
