Subjects and their family members have been studied with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive non-malignant lymphadenopathy, defective lymphocyte programmed cell death, or apoptosis, expanded populations of TCRalpha-beta CD3+, CD4-, CD8- lymphocytes, and autoimmune phenomena. Most patients have unique, deleterious mutations 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 requires 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 Hodgkinis 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 Hodgkinis disease is being pursued. In addition a transgenic mouse model of dominant negative Fas mutations was developed. Constructs placing mutant Fas alleles under the control of the actin promoter have been used to generate transgenic mice. Differences in the background strains of mice which combine with mutated Fas to produce overt autoimmunity are being studied.
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