| SLE is a phenotypically diverse, multi-system autoimmune disorder that is caused by ill-defined interaction(s) between environmental and genetic factors. Genome wide linkage analysis of SLE multiplex families suggests there is significant racial and genetic heterogeneity, further complicating the genetic dissection of this disorder. Fortunately, there are phenotypically similar mouse models of lupus; including genetically engineered and spontaneous models. Most of the investigative work in the field has focused on identifying disease susceptibility loci; however, there are experimental data that suggest disease resistance genes are also important, The non-autoimmune New Zealand White (NZW) mouse does not develop lupus despite harboring the best characterized lupus susceptibility intervals and a disease permissive major histocompatibility locus H-2z/z suggesting that the NZW genome contains allelic polymorphisms that negatively regulate the phenotypic expression of lupus susceptibility gene(s). We hypothesize that experimental crosses between NZW and C57BL/6.FcgammaRIIB-deficient mice will allow the identification of NZW-derived intervals that attenuate the lupus phenotypes in this genetically engineered murine model of lupus. We are 1) mapping quantitative trait loci (QTL) that modulate the FcgammaRIIB-/- lupus phenotype in order to identify NZW-derived intervals that are associated with suppression of the phenotype and 2) we will then construct chromosome substitution strains (CSS) in order to dissect the genetic contribution of these individual QTL. Identification of QTL that modulate the lupus phenotype and the subsequent development of QTL containing CSS will lay the foundation for the future functional assessment of the lupus-attenuating QTL and for candidate gene analysis. Understanding the genetic basis of disease resistance could facilitate the development of novel therapeutic approaches for treating this devastating disease. |