Systemic lupus erythematosus (SLE) affects millions of people in the United States. Development of SLE is multi-factorial, including both genetic and environmental influences. Fas and FasL genes are critical regulators involved in SLE development by inducing death of activated lymphocytes. A single defect in either gene causes lethal SLE-like disease. Although the general scheme of Fas-based mechanism is widely accepted, the intricate interactions among various components of the immune system remain largely unexplored. Understanding these molecular mechanisms will be crucial for future development of better prevention and treatment of SLE. Ulcerative colitis is an inflammatory bowel disease (IBD) that, like SLE, has genetic elements and environmental factors for its development. Studies of II-2 and II-2Ralpha gene knockout mice reveal an interesting association of several immune-based diseases with the gene defects. These mice develop""""""""autoimmune-like"""""""" disease characterized by a mild lymphadenopathy, infiltration of lymphocytes into several organs, autoimmune hemolytic anemia and ulcerative colitis. Two major hypotheses have been proposed. One believes that IL-2 is critical for the induction of lymphocyte death by regulating apoptosis-promoting and apoptosis-preventing molecules. The second hypothesis proposes that IL-2 is regulating CD25+CD4 + regulatory T cells that are critical to the containment of autoimmune response. Despite no simple treatment can cure these diseases, we have been able to cure both diseases-induced end organ failure and lethality in animal models by using genetic approach. When we bred the fas mutant gene into the IL-2 knockout recipients, the lethality imposed by either gene was inhibited. We hypothesize that IL-2 is the most important lymphokine required for the development of autoimmune lymphocytes in Ipr mice and that Fas-mediated apoptosis is critical for the life-threateninq end-orqan patholoqy of the ulcerative colitis. In these protected mice, there are numerous interesting phenotypes that have implications in the development of the disease, their participating components, and their mechanisms of action. The goals of the application are to prove the hypothesis and to further understand the regulatory mechanisms responsible for the protection a0ainst the mutant gene-imposed lethality.
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