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, Ofer Mandelboim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageAmerican English
Pages (from-to)44151-44160
Number of pages10
JournalOncotarget
Volume6
Issue number42
DOIs
StatePublished - 2015

Keywords

  • ADAM17 deficiency
  • ADCC
  • CD16
  • Immune response
  • Immunity
  • Immunology and microbiology section
  • NK cells

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