Sjogren's syndrome (SS) is characterized by lymphocytic infiltration of the salivary glands leading to a variety of dental complications. This project focuses on molecular abnormalities in IL-2 biology involving SS T cells. T lymphocytes from SS peripheral blood are hyporesponsive to mitogenic and antigenic stimuli, whereas T lymphocytes infiltrating the SS salivary glands actively produce IL-2. Some of these are older observations based on cell activation markers; others are recent findings from our own laboratory measuring transcription factors or using PCR amplification in SS salivary gland tissue. The current specific aims which follow are designed to further analyze abnormalities of signal transduction in relation to a defect in the Oct. 1 transcription factor necessary for IL-2 gene activation, to continue our analysis of cytokine profiles using PCR, and to develop new therapeutic modalities for SS.
Specific aims : 1. The expression of nuclear proteins binding to cognate DNA sequences in the IL-2 gene promoter region (transcription factors) will be assessed by electrophoretic mobility shift assay. This signaling event is putatively the most distal in the pathway. Therefore, abnormalities detected would support our hypothesis that an early signaling defect in calcium contributes to the reduced biosynthesis of IL-2. 2. Specific mRNAs for the gene encoding IL-2 will be studied in SS salivary glands using the PCR. Demonstration of inflammatory cytokines such as IL-2 in SS tissues could provide an explanation for the intense lymphocytic infiltration and tissue destruction. 3. Normalization of IL-2 biosynthesis, as well as the expression of proteins involved in the regulation of the IL-2 gene, will be attempted using drugs known to enhance T cell activation. Aspirin-like drugs that enhance L-2 production and both early and late signaling events will be studied.
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