DEFICIENCY OF THE FAS APOPTOSIS PATHWAY WITHOUT FAS GENE-MUTATIONS INPEDIATRIC-PATIENTS WITH AUTOIMMUNITY LYMPHOPROLIFERATION/

Fas (CD95) is a transmembrane molecule that induces programmed cell de ath (PCD) of lymphocytes. We examined its function in children with ch ronic thrombocytopenia, serum autoantibodies, and lymphadenopathy and/ or splenomegaly. We found that T-cell lines from six of seven patients with this autoimmune/lymphoproliferative disease (ALD) were relativel y resistant to PCD induced by monoclonal antibodies to Fas. By contras t, Fas function was normal in control patients with typical chronic id iopathic thrombocytopenic purpura (ITP) without lymphadenopathy. The d efect was not due to decreased Fas expression, nor to over-production of soluble forms of Fas. Moreover, it specifically involved the Fas sy stem because PCD was induced in the normal way by methylprednisolone. Complementary DNA sequencing of the Fas gene did not identify any caus al mutation in patients with ALD. This distinguished them from patient s with the human autoimmune lymphoproliferative syndrome (ALPS), who c arry mutations of the Fas gene. Moreover, patients with ALD did not sh ow the peripheral expansion of CD4/CD8 double-negative T cells that ch aracterizes the ALPS phenotype. Fas signaling involves activation of a sphingomyelinase-catalyzing production of ceramide. We found that cer amide-induced PCD was defective in patients with ALD and not in patien ts with typical chronic ITP. These data suggest that the ALD patient d efect involves the Fas signaling pathway downstream from the sphingomy elinase and that Fas gene mutations and double-negative T-cell expansi on are not the only signs of a defective Fas system. (C) 1997 by The A merican Society of Hematology.