This project is based on our discovery that genetic mutations in molecules that control the programmed death, or apoptosis, of lymphocytes is responsible for the Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a disease affecting children that leads to loss of normal lymphocyte homeostasis leading to swollen lymph glands and organs. Because lymphocytes are the primary cell mediating immune reactions, this excess of lymphocytes leads to a pathological autoimmune attack on the patient?s own tissues. We have identified mutations in a death-inducing cell surface receptor termed Fas (also known as APO-1 or CD95) and, in the past year, proteolytic enzymes that are crucial to lymphocyte programmed cell death. We identified the structural alterations in the Fas receptor proteins encoded by the patients? mutations by nuclear magnetic resonance. These studies promise to provide new insights into the molecular mechanisms that underlie autoimmune disease as well as revealing crucial steps in the pathway of programmed cell death in lymphocytes. - ALPS, apoptosis, propriocidal regulation, Fas, TNF, caspase, autoimmunity, lymphocyte - Human Subjects
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