title: Defective apoptosis in lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias.
abstract: Fas-mediated signaling is important for lymphocyte elimination. We investigated lymphocytes for Fas-signaling defects in 20 pediatric patients with chronic hematologic autoimmunity. In 5 of 20 (25%), there was profound resistance to exogenous FasL-mediated lysis, Fas mAb, and anti-CD3. FasL function, though variable, was not significantly different from that of simultaneously evaluated controls. Only 1 patient had a Fas mutation and manifestations of autoimmune lymphoproliferative syndrome. In contrast, lymphocytes from his clinically normal mother with the same mutation were normally sensitive to FasL. In 3 patients, normal Fas-mediated lysis was restored with rhIL-2. IL-2 had no effect in the other 2 patients. Activation and proliferation functions of IL-2 were normal in all 5. We conclude that altered Fas signaling, independent of Fas mutations, can precipitate hematologic autoimmunity. IL-2 can rescue some lymphocytes from this defect. In IL-2 refractory cases, a persistently defective response to IL-2 continues to confer a lymphocyte survival advantage. Hence, altered Fas pathway signaling with or without defective IL-2 responses should be considered in the etiology of hematologic autoimmunity.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shenoy
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: T
authors.initials: T
authors.lastname: Chatila
authors.forename: J
authors.initials: J
authors.lastname: Tersak
authors.forename: B
authors.initials: B
authors.lastname: Duffy
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: A R
authors.initials: AR
authors.lastname: Thilenius
authors.forename: J H
authors.initials: JH
authors.lastname: Russell
mesh_terms: D000293:Adolescent; D000744:Anemia, Hemolytic, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019014:fas Receptor