: Considerable progress has been made in the understanding of human immune-system diseases through the study of animal model systems. The availability of spontaneous inherited mutations in inbred mouse strains have proven to be an invaluable resource in the development of these models. For example, the beige mutation in mice and Chediak-Higashi syndrome in humans arise from mutations in the same gene. Induced mutations have also been used to successfully model human diseases. Among the immunologically relevant mouse models is the X-linked mutation scurfy (sf). Males hemizygous for the sf mutation develop a severe autoimmune lymphoproliferative disease that is fatal by 20-24 days of age. The mice exhibit several gross morphological abnormalities including runting and exfoliate dermatitis. They also develop lymphocytic infiltrates at several sites, including lymph nodes, spleen, liver, lungs and skin. Initial experiments have shown that these symptoms are the result of chronic in vivo T cell activation, with subsequent overproduction of a wide variety of cytokines. While available data point to a T cell defect in sf mice, the underlying mechanism remains to be elucidated. There are two possible explanations for the T cell defect seen in these mice. First, the sf gene product is involved directly in TCR signal transduction, and the sf mutation results in dysregulated TCR activation. Second, the sf product is involved in a pathway, such as the CTLA-4 pathway, that regulates TCR activation. The gene that is mutated in these mice has been cloned and shown to be a member of the forkhead/winged-helix family of transcriptional regulators. T cells from mice that overexpress this gene are non-responsive to activating stimuli, supporting the notion that this gene regulates T cell function. Mutations in this gene result in the human IPEX syndrome, where affected males die in their first year of an autoimmune disease. It is not immediately apparent how mutations in this gene have such a dramatic affect on T cell activation. The experiments in this application will determine where in the T cell activation pathway Scurfin (the name given to the protein) acts. We will also determine its role in regulating cytokine gene expression and in regulating peripheral T cell activation. These analyses will shed light on the regulatory pathways involved in the development of autoimmune disease, and will serve as a model for human immune-system abnormalities.
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