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Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
Published on: May 22, 2020
Cytokine secretion and NK cell activity in human ADAM17 deficiency
Pinchas Tsukerman1, Eli M Eisenstein2, Maor Chavkin2
1Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, Israel.
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.
Insights
A rare genetic deficiency in ADAM17 impairs cytokine secretion and impacts natural killer (NK) cell function. This suggests caution is needed when using ADAM17 inhibitors, due to potential severe side effects.
Area of Science:
- Immunology
- Genetics
Background:
- Genetic deficiencies offer crucial insights into human gene function.
- ADAM17 (a disintegrin and metalloproteinase domain-containing protein 17) plays a role in protein shedding.
- Natural Killer (NK) cells are critical for innate immunity.
Observation:
- A patient with a rare genetic deficiency in ADAM17 exhibited impaired peripheral blood mononuclear cell (PBMC) cytokine secretion upon lipopolysaccharide (LPS) stimulation.
- This impairment correlated with severe bacteremia, suggesting a link between ADAM17 function and host defense.
- ADAM17 was identified as a protease that cleaves CD16, a key receptor on NK cells.
Findings:
- Patient's NK cells showed normal expression of activating receptors and maintained high surface CD16 levels post-monoclonal antibody (mAb) stimulation.
- While NK cell potency increased upon direct CD16 activation, Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) assays showed no significant difference.
- The study highlights a specific role for ADAM17 in regulating CD16 shedding and subsequent NK cell responses.
Implications:
- ADAM17 inhibitors, being developed to enhance CD16 activity, may carry risks of severe side effects due to compromised cytokine secretion.
- Clinical application of ADAM17 inhibitors requires careful consideration of potential immunomodulatory consequences.
- Understanding ADAM17's role in NK cell regulation is vital for developing safer immunotherapies.
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