Systemic lupus erythematosus (SLE) is an autoimmune disorder of largely unknown etiology characterized by profound T cell effector dysfunction. SLE T cells produced reduced amounts of interleukin 2 (IL-2) which contributes to the increased rate of infections, decreased generation of cytotoxic and regulatory T cells and decreased ability to eliminate autoreactive T cells through activation-induced cell death. IL-2 production is controlled at the transcription level by factors whose activity is influenced by membrane-initiated signaling events. In parallel, T cells from patients with SLE produced increased amounts of the proinflammatory cytokine IL-17. Studies in human SLE T cells which display increased levels of the transcriptional repressor, cAMP responsive element modulator (CREM) and mice made to overexpress or lack CREM, established that CREM is a transcriptional repressor for IL-2 and a transcriptional enhancer for IL-17. This bidirectional effect is accomplished through epigenetic modifications of the IL-2 and IL-17 loci. A shorter form of CREM, ICER, was found to be responsible for the increased production of IL-17 and to accomplish this through distinct metabolic events. The studies will advance by generating ICER-specific deficient mice and T cell-restricted ICER specific-deficient mice to study the role of ICER in the development of autoimmunity and by determining the role of ICER/CREM in lymphocyte metabolism. The overall direction will be to define the metabolic pathways that account for the apparent effector cell phenotype in autoimmunity. In this way we will identify specific metabolic targets which will mitigate autoimmune pathology.
Systemic lupus erythematosus afflicts more than one million Americans most of whom are women in the child-bearing age. Diagnosis is frequently delayed and the disease has significant morbidity and mortality and current treatment is based primarily on indiscriminate immunosuppression. The proposal will characterize mechanisms that lead to decreased production of an important lymphokine, interleukin-2 and the increased production of a proinflammatory lymphokine, interleukin-17. Successful completion of the proposed studies will lead to the identification of novel treatment targets.
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