title: Cytokine secretion and NK cell activity in human ADAM17 deficiency.
abstract: Genetic deficiencies provide insights into gene function in humans. Here we describe a patient with a very rare genetic deficiency of ADAM17. We show that the patient's PBMCs had impaired cytokine secretion in response to LPS stimulation, correlating with the clinical picture of severe bacteremia from which the patient suffered. ADAM17 was shown to cleave CD16, a major NK killer receptor. Functional analysis of patient's NK cells demonstrated that his NK cells express normal levels of activating receptors and maintain high surface levels of CD16 following mAb stimulation. Activation of individual NK cell receptors showed that the patient's NK cells are more potent when activated directly by CD16, albeit no difference was observed in Antibody Depedent Cytotoxicity (ADCC) assays. Our data suggest that ADAM17 inhibitors currently considered for clinical use to boost CD16 activity should be cautiously applied, as they might have severe side effects resulting from impaired cytokine secretion.
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Pinchas
authors.initials: P
authors.lastname: Tsukerman
authors.affiliation: Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem il, Israel.
authors.forename: Eli M
authors.initials: EM
authors.lastname: Eisenstein
authors.affiliation: Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem il, Israel.
authors.forename: Maor
authors.initials: M
authors.lastname: Chavkin
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmiedel
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Wong
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Marion
authors.initials: M
authors.lastname: Werner
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Barak
authors.initials: B
authors.lastname: Yaacov
authors.affiliation: Pediatric Infectious Diseases Unit, Hadassah-Hebrew University Medical Center, Ein Kerem, Kiryat Hadassah, Jerusalem, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Averbuch
authors.affiliation: Department of Dermatology, Hadassah Hebrew University Medical Center, Ein Kerem, Kiryat Hadassah, Jerusalem, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Molho-Pessach
authors.affiliation: Pediatric Hemato-Oncology and Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Ein Kerem, Kiryat Hadassah, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Kaynan
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Bar-On
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Seidel
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yamin
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D000072198:ADAM17 Protein; D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D017809:Fatal Outcome; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D010641:Phenotype; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D008070:Lipopolysaccharides; D017452:Receptors, IgG; D051722:ADAM Proteins; D000072198:ADAM17 Protein
keywords: ADAM17 deficiency; ADCC; CD16; Immune response; Immunity; Immunology and Microbiology Section; NK cells