Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease
Schafiq Nabhani,
Sebastian Ginzel,
Hagit Miskin,
Shoshana Revel-Vilk,
Dan Harlev,
Bernhard Fleckenstein,
Andrea Hönscheid,
Prasad T. Oommen,
Michaela Kuhlen,
Ralf Thiele,
Hans-Jürgen Laws,
Arndt Borkhardt,
Polina Stepensky,
Ute Fischer
Affiliations
Schafiq Nabhani
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Sebastian Ginzel
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
Hagit Miskin
Pediatric Hematology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
Shoshana Revel-Vilk
Department of Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Dan Harlev
Pediatric Hematology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
Bernhard Fleckenstein
Department of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
Andrea Hönscheid
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Prasad T. Oommen
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Michaela Kuhlen
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Ralf Thiele
Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany
Hans-Jürgen Laws
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Arndt Borkhardt
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Polina Stepensky
Department of Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Ute Fischer
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
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.
