Our primary research interest concerns the genetic analysis of systemic lupus erythematosus (SLE) susceptibility using the mouse as a model. The long term goals of our research is to identify the genes responsible for SLE-susceptibility, characterize their contribution to autoimmunity, and understand how their interactions result into the well described SLE immunopathology. This is a multifaceted project combining immunological and genetic techniques and reagents, using the mouse as the best immunologically and genetically characterized model system.

The complex, polygenic inheritance of SLE susceptibility makes it difficult to identify and functionally characterize the genes involved. Typical linkage analyses localize susceptibility loci to intervals of about 20 cM, even when hundreds of testcross animals are analyzed. Although linkage analyses have been an essential first step, providing necessary information about the number and locations of susceptibility genes in SLE-prone strains, they have supplied little concerning the nature of the component phenotypes each locus contributes in lupus susceptibility and cannot be used for significant refinement of their genetic maps. The essential problems stem from the fact that no single gene is required for the expression of the trait (here SLE) and the expression of disease is uncoupled from the genotype by the requirement of undefined environmental triggering events, resulting in incomplete penetrance (i.e., not all individuals carrying the susceptibility genotypes are affected). Similarly, it is difficult to associate specific phenotypes with individual loci when several genes effecting the samephenotypes are segregating simultaneously. To address these issues, we have produced a series of congenic strains carrying susceptibility loci on a non-autoimmune background and we are using use these strains to dissect the genetics of SLE susceptibility.

Our immediate focus of interest is to characterize two chromosomal regions on telomeric chromosomes 1 and 4. We initially identified these regions as containing a strong SLE-susceptibility locus by linkage analysis (Sle1 and Sle2, respectively), and we have associated them with a distinct component of SLE autoimmune processes: loss of tolerance to chromatin for Sle1, and polyclonal B cell activation for Sle2. Subsequent analysis has shown that these two regions contain multiple susceptibility loci, a phenomenon that is being described in other murine models of polygenic disease such as diabetes and epilepsy. I have produced a series of strains containing congenic sub-intervals that we use to produce high resolution genetic maps of these loci, and to understand the functional interactions of closely-linked weak loci resulting in a strong susceptibility locus. This constitutes a crucial point to understand not only SLE-susceptibility, but also the genetics of other polygenic diseases.

In a broader view, we are interested in using the vast array of conceptual tools and reagents of mouse genetics to address biological problems.