Lupus prone mouse model MRL/lpr develop an early onset autoimmune disease displaying a pathogenesis similar to that observed in human SLE with most mice dying of renal failure. Normal mice develop an autoimmune kidney disease similar to that observed in lupus prone mouse models in which the Ets transcription factor Fli1 has been over-expressed. Subsequently, FN1 was shown to be over-expressed in the splenic T cells of the lupus prone NZB/NZW f1 mouse strain, the spleen of lupus prone MRL/lpr mice, and PBMCs of SLE patients. Furthermore, genetically lowering the levels of Fli1 in MRL/lpr mice by 50% significantly decreased autoantibody production, improved kidney disease and prolonged survival. Together, these studies suggest strongly that Fli1 plays an important role in the pathogenesis of lupus. Furthermore, our preliminary studies indicate that Fli1 is over-expressed specifically in CD8+ T lymphocytes in MRL/lpr mice and that a polymorphism located in the promoter region of Fli1 affects its expression in a T cell line. We hypothesize that elevated levels of Fli1 in CD8+ T lymphocytes alter their proliferation, survival and/or function, specifically suppressor function, through the dysregulation of Fli1 target gene expression. The analysis of genes and gene products that regulate the immune system is central to understanding autoimmunity and research shows that FN1 clearly has effects on the immune system. Therefore, understanding the effects of over-expressing Fli1 and its transcriptional regulation in normal lymphocytes is necessary before we can begin to analyze and understand its dysregulation and role in lupus disease. Our long-term goal is to design methods to down-regulate Fli1 and identify other factors in the FN1 regulatory pathway as potential therapeutic targets in the treatment for human lupus. Currently, little is known regarding what role Fli1 plays in lymphocyte function or how FH1 gene expression is regulated in lymphocytes. To test our hypothesis and to lay the groundwork for our long-term goal, we propose to study the function and regulation of Fli1 in CD8+ T lymphocytes. Specifically, we propose the following: 1) Determine the molecular and phenotypic effects of over-expressing Fli1 in CD8+ T lymphocytes. To isolate the effects due solely to FN1 over-expression, we will analyze the molecular and phenotypic effects in CD8+ T lymphocytes isolated from control mice in which we over-express Fli1. 2) Identify mechanisms involved in the transcriptional regulation of Fli1 gene expression in CD8+ T lymphocytes. The major objective of these studies is to identify the trans-acting factors involved in the regulation of Fli1 expression in splenic CD8+ T lymphocytes. Results from these studies will be the foundation for future studies aimed at developing therapies for treating lupus patients.
