Thirty-three unrelated children and their families have been studied with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive non-malignant lymphadenopathy, autoim-mune phenomena and expanded populations of TCR/CD3+, CD4-, CD8- lymphocytes. These findings are due to a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, in turn caused by defects of lymphocyte apoptosis. Fifteen children were found to have defective Fas-mediated T lymphocyte apoptosis, and in 13 of these children a unique, deleterious mutation was found in the Fas gene. The heterozygous mutations produce defective protein with a dominant negative effect on apoptosis when they are co-expressed with normal Fas. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients indicates an involvement of Fas in this newly recognized disorder. Family studies demonstrate that the inheritance of the mutant Fas alleles causes a dominantly inherited cellular apoptosis defect. However, overt autoimmunity appears to require additional factors besides heterozygous Fas mutation. Further studies of family members revealed multiple extended families in which a dominant negative Fas mutation segregated with clinical abnormalities ranging from benign lymphadenopathy to autoimmune disease with elevated double negative T cells to Hodgkin!s disease and non-Hodgkin's lymphoma. The possibility that Fas and other proteins which participate in lymphocyte apoptosis might function as oncogenes in the development of Hodgkin's disease is being pursued. In addition a transgenic mouse model of dominant negative Fas mutations is being developed. Constructs placing mutant Fas alleles under the control of the actin promoter have been used to generate transgenic mice in which expression studies are being undertaken.
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