Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that occurs primarily in women (9:1 compared to men) during their childbearing years. In the United States, the prevalence of SLE ranges from 14.6 to 50.8 cases per 100,000 people. The strongest risk factor for the onset of SLE is female gender. The development and progression of SLE is postulated to involve abnormal regulation of T cell functions that are influenced by estrogen receptor-dependent stimulation of T cell activation molecules. Estrogen receptors are ligand activated transcription factors that bind to specific sequences along the DNA of target genes and alter the rate of transcription. Calcineurin and CD 154, key regulators of intracellular signaling, are increased by estrogen only in the T cells from women with SLE. The long-term goals of this project are to identify steroid hormone controlled gene regulatory networks that alter lymphocyte function and contribute to the propensity of women to develop autoimmune diseases. The objective of this application is to investigate the molecular mechanisms by which estrogen upregulates signal transduction molecules in SLE T cells thereby contributing to atypical T-B cell interactions and SLE pathogenesis. The first goal is to test the hypothesis that the estrogen-dependent sensitivity is due to differences in the quantity of estrogen receptor subtypes in female SLE T cells compared with normal T cells. The second goal is to investigate the molecular basis of estrogen receptor regulation of calcineurin and CD 154 expression in SLE T cells. The third goal is to test if the estrogen-dependent sensitivity in SLE T cells is due to molecular linkage between the estrogen receptor and the mitogen activated protein kinase (MAPK) signal transduction pathway in SLE T cells. A combination of molecular and immunological approaches will be used to analyze cultured T cells obtained from SLE patients and normal individuals in order to achieve these goals. The findings from the proposed research are expected to provide new insight into gender-biased autoimmunity and lead to new therapeutic approaches to improve the quality of patient's lives.
