ROLE OF THE FAS/FAS LIGAND SYSTEM IN APOPTOSIS AFTER ENVIRONMENTAL TRAUMA

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Lpr and gld mice have phenotypic and functional abnormalities resembling human SLE due to abnormal Fas and Fas ligand (Fas L) apoptosis genes, respectively. Apoptosis is a form of programmed cell death and is necessary for the elimination of self-reactive lymphocytes from the immune system. The surprising finding that Fas is involved in radiation- induced apoptosis suggests a new role for the Fas/Fas L system in deleting cells following environmental trauma. This proposal will define the role of Fas/Fas L in apoptosis after gamma irradiation using a short term in vitro culture system. The regulation of Fas expression on injured cells of normal and lpr mice will be studied by examining Fas expression and transcription after irradiation. In vivo short term chimera experiments and in vivo cytotoxicity assays will determine if the Fas expressed is functional. The effect of the lpr mutant form of Fas on p53 levels will be examined before and after irradiation in cells from lpr mice, since p53 is a key mediator of radiation-induced apoptosis. It will be determined if mechanisms of cell injury other than gamma irradiation, such as heat shock and UV irradiation involve the Fas/Fas L system. These experiments will define the role of Fas/Fas L in tissue injury and may help clarify its role in systemic autoimmunity.