title: Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.
abstract: Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Schafiq
authors.initials: S
authors.lastname: Nabhani
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ginzel
authors.affiliation: Pediatric Hematology Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Miskin
authors.affiliation: Department of Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Revel-Vilk
authors.affiliation: Pediatric Hematology Unit, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Harlev
authors.affiliation: Department of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fleckenstein
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hönscheid
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Prasad T
authors.initials: PT
authors.lastname: Oommen
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhlen
authors.affiliation: Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Thiele
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Laws
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Department of Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany ute.fischer@med.uni-duesseldorf.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics / Q000276:immunology*; D053455:Caspase 10 / Q000235:genetics / Q000276:immunology; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D018389:Codon, Nonsense; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D008297:Male; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: D018389:Codon, Nonsense; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C508438:IL12RB1 protein, human; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D019014:fas Receptor; D018664:Interleukin-12; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; C506438:CASP10 protein, human