ABSTRACT
BACKGROUND: Impaired Fas-induced apoptosis of lymphocytes in vitro is a principal feature of the autoimmune lymphoproliferative syndrome (ALPS). We studied six children with ALPS whose lymphocytes had normal sensitivity to Fas-induced apoptosis in vitro. METHODS: Susceptibility to Fas-mediated apoptosis and the Fas gene were analyzed in purified subgroups of T cells and other mononuclear cells from six patients with ALPS type III. RESULTS: Heterozygous dominant Fas mutations were detected in the polyclonal double-negative T cells from all six patients. In two patients, these mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells. CONCLUSIONS: Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death.
Subject(s)
Autoimmune Diseases/genetics , Lymphoproliferative Disorders/genetics , Mutation , fas Receptor/genetics , Adolescent , Apoptosis , Autoimmune Diseases/classification , Cells, Cultured , Child , DNA Mutational Analysis , Female , Gene Expression , Hematopoiesis/genetics , Hematopoiesis/physiology , Heterozygote , Humans , Lymphoproliferative Disorders/classification , Male , Mosaicism , Phenotype , Polymerase Chain Reaction , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , T-LymphocytesABSTRACT
Fas-induced apoptosis, a key event in the regulation of lymphocyte homeostasis, is mainly mediated by the activation of a cascade of caspases. Using caspase- and Fas-associated death domain protein-deficient Jurkat cell lines as well as a pan-caspase inhibitor (Z-VAD-fmk), we observed a second Fas-induced cell death event, independent of any known caspase activation. This pathway is of slow kinetics and displays some features of necrosis. However, this caspase-independent pathway does not seem to play a significant role in the Fas-mediated death of primary activated T cell blasts. Indeed, in this setting, Fas-induced cell death was always substantially inhibited by Z-VAD-fmk, suggesting that caspase activation is an absolute requirement in the Fas-induced death of primary human T lymphocytes.