Inbred laboratory mouse strains have proven essential for research into systemic autoimmune diseases because the inbred genotype provides a genetically uniform animal for experimental purposes. However, there is restricted genetic heterogeneity among common laboratory strains primarily due to the origination from two original Asian and European fancy mice. This has significantly reduced the diversity of common genetic variants that are thought to contribute significantly to complex traits such as systemic autoimmunity. We propose that the Collaborative Cross (CC) Recombinant Inbred (RI) panel is the best suited to model the range of phenotypes in complex diseases because it is the only experimental mammalian resource with genome-wide genetic variation randomized across a large, heterogeneous and reproducible population. Significantly, the CC RI panel adds the genomes of three wild strains from three different continents that are not represented in the common inbred strains. Consequently, the CC strains provide a powerful tool to model autoimmunity in a much more genetically diverse panel than previously available. We therefore hypothesize that the much greater genetic heterogeneity of CC strains, including contributions from wild-derived strains, will allow development of a wide range of immunological and pathological features from apparent good health to systemic autoimmunity. Furthermore, we posit that this will be amenable to genotyping and quantitative trait locus (QTL) analysis in a way not possible with previous approaches. This is supported by our preliminary studies, which show that CC strains exhibit differing levels of spontaneous anti-nuclear autoantibodies (ANA) and inflammatory biomarkers, allowing them to be grouped into a number of phenotypes. Furthermore, the presence of wild-derived strains contributed to the mapping of ANA positivity to loci on chromosomes 1 and 17. We believe that investigation of the profiles of immune mediators, cellular inflammation, autoantibodies, and pathology in the CC RI panel will lead to the identification of a more diverse spectrum of autoimmune phenotypes than currently available. Additionally, we argue that analysis of the different autoimmune phenotypes among CC RI strains will enhance our ability to identify specific genes and molecular and cellular pathways that discriminate steps in the progression from apparent good health, to sub-clinical inflammation and/or autoimmunity, to systemic autoimmune disease. We will address this in two aims. Specific Aim 1: Development of systemic autoimmunity in CC RI strains, and Specific Aim 2: Genetic mapping of systemic autoimmunity in CC RI mice. Successful completion of these studies should result in identifying new strains of mice to study the progression of autoimmunity from apparent good health to systemic disease, a better understanding of the genetics, biomarkers, and pathogenesis of systemic autoimmunity, and identification of potential therapeutic ta...