Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome

GH Fisher, FJ Rosenberg, SE Straus, JK Dale… - Cell, 1995 - cell.com
GH Fisher, FJ Rosenberg, SE Straus, JK Dale, LA Middelton, AY Lin, W Strober, MJ Lenardo
Cell, 1995cell.com
Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome
(ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune
phenomena, and expanded populations of TCR-CD3+ CD4-CD8-lymphocytes. These
findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal
immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each
child had defective Fas-mediated T lymphocyte apoptosis associated with a unique …
Summary
Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+ CD4-CD8-lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.
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