Oncotarget

Research Papers: Immunology:

Cytokine secretion and NK cell activity in human ADAM17 deficiency

Pinchas Tsukerman, Eli M. Eisenstein, Maor Chavkin, Dominik Schmiedel, Eitan Wong, Marion Werner, Barak Yaacov, Diana Averbuch, Vered Molho-Pessach, Polina Stepensky, Noa Kaynan, Yotam Bar-On, Einat Seidel, Rachel Yamin, Irit Sagi, Orly Elpeleg and Ofer Mandelboim _

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Oncotarget. 2015; 6:44151-44160. https://doi.org/10.18632/oncotarget.6629

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Abstract

Pinchas Tsukerman1,*, Eli M. Eisenstein2,*, Maor Chavkin2, Dominik Schmiedel1, Eitan Wong3, Marion Werner4, Barak Yaacov4, Diana Averbuch5, Vered Molho-Pessach6, Polina Stepensky7, Noa Kaynan1, Yotam Bar-On1, Einat Seidel1, Rachel Yamin1, Irit Sagi3, Orly Elpeleg4 and Ofer Mandelboim1

1 Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel

2 Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem il, Israel

3 Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

4 Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel

5 Pediatric Infectious Diseases Unit, Hadassah-Hebrew University Medical Center, Ein Kerem, Kiryat Hadassah, Jerusalem, Israel

6 Department of Dermatology, Hadassah Hebrew University Medical Center, Ein Kerem, Kiryat Hadassah, Jerusalem, Israel

7 Pediatric Hemato-Oncology and Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Ein Kerem, Kiryat Hadassah, Jerusalem, Israel

* These authors have contributed equally to this work

Correspondence to:

Ofer Mandelboim, email:

Keywords: ADAM17 deficiency, NK cells, CD16 , ADCC, Immunology and Microbiology Section, Immune response, Immunity

Received: August 26, 2015 Accepted: November 21, 2015 Published: December 16, 2015

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.


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