(provided by candidate): Systemic Lupus Erythematosus (SLE) is an autoimmune disease of uncertain etiology that is influenced not only by genetic but also by environmental factors. Particularly the latter remain poorly understood. Development of nephritis is a prominent feature in SLE, contributing substantially to morbidity and mortality. Present treatment options for nephritis are limited and associated with significant toxicity. Better understanding of the pathogenesis of renal disease in SLE may lead to the development of new, less toxic therapies. Pristane injected intraperitoneally (i.p.) into mice genetically not prone to autoimmune disease induces the production of lupus specific autoantibodies, including anti-DNA/chromatin, and immune complex nephritis. In preliminary studies we have found that IFNg and IL-6 are essential for both the production of these antibodies and the nephritis, but that nephritis may develop prior to the antibody response. We hypothesize that anti-DNA/chromatin autoantibodies are a marker for overproduction of inflammatory cytokines which promote nephritis, rather than the cause of renal disease in pristane-induced lupus. We propose to examine the temporal relationship between the production of autoantibodies and the development of nephritis in pristane-treated mice. Outcome of this study will answer whether anti-DNA/chromatin antibodies are obligatory for the development of nephritis or whether other factors are involved in development of renal disease. In an effort to determine if dysregulated cytokine homeostasis is sufficient to induce the production of autoantibodies and nephritis we plan to induce their constitutive expression by bone marrow derived cells. The proposed experiments will involve the transduction of hematopoietic stem cells with retroviral vectors encoding IFNg, IL-6 or both for later injection into mice. We predict that with this approach we will be able to induce autoantibody production and nephritis. Finally we aim to define the roles of ITAM vs ITIM containing Fc receptors for the development of nepliritis.We will initially study of the effect of FcgRI/III and FcgRII deficiency on pristane-induced lupus. Subsequently anti-DNA/chromatin antibody production and nephritis after pristane-treatment in FcgRI/III deficient mice over expressing IFNg or IL-6 and FcgRII deficient mice also deficient in IFNg or IL-6 will be studied. The out come of these experiments will determine if Fc receptor mediation is obligatory for the development of nephritis or whether a direct effect of cytokines alone is sufficient for the induction of renal disease. Based on our preliminary data we expect that Fc receptor signaling is the critical varialble for the induction of renal disease.
