Deficiency of the Fas Apoptosis Pathway Without Fas Gene Mutations in Pediatric Patients With Autoimmunity/Lymphoproliferation

Author:

Dianzani Umberto1,Bragardo Manuela1,DiFranco Daniela1,Alliaudi Carla1,Scagni Paola1,Buonfiglio Donatella1,Redoglia Valter1,Bonissoni Sara1,Correra Antonio1,Dianzani Irma1,Ramenghi Ugo1

Affiliation:

1. From the Dipartimento di Scienze Mediche, Dipartimento di Scienze Pediatriche e dell' Adolescenza, and Divisione Universitaria di Ematologia, Dipartimento di Medicina ed Oncologia Sperimentale, Università di Torino, Novara; and Divisione di Pediatria, Ospedale S. S. Annunziata, Napoli, Italy.

Abstract

Abstract Fas (CD95) is a transmembrane molecule that induces programmed cell death (PCD) of lymphocytes. We examined its function in children with chronic 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 relatively resistant to PCD induced by monoclonal antibodies to Fas. By contrast, Fas function was normal in control patients with typical chronic idiopathic thrombocytopenic purpura (ITP) without lymphadenopathy. The defect was not due to decreased Fas expression, nor to over-production of soluble forms of Fas. Moreover, it specifically involved the Fas system because PCD was induced in the normal way by methylprednisolone. Complementary DNA sequencing of the Fas gene did not identify any causal mutation in patients with ALD. This distinguished them from patients with the human autoimmune lymphoproliferative syndrome (ALPS), who carry mutations of the Fas gene. Moreover, patients with ALD did not show the peripheral expansion of CD4/CD8 double-negative T cells that characterizes the ALPS phenotype. Fas signaling involves activation of a sphingomyelinase-catalyzing production of ceramide. We found that ceramide-induced PCD was defective in patients with ALD and not in patients with typical chronic ITP. These data suggest that the ALD patient defect involves the Fas signaling pathway downstream from the sphingomyelinase and that Fas gene mutations and double-negative T-cell expansion are not the only signs of a defective Fas system.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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