Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations

Jordan S Orange; Scott R Brodeur; Ashish Jain; Francisco A Bonilla; Lynda C Schneider; Roberto Kretschmer; Samuel Nurko; Wendy L Rasmussen; Julia R Köhler; Stephen E Gellis; Betsy M Ferguson; Jack L Strominger; Jonathan Zonana; Narayanaswamy Ramesh; Zuhair K Ballas; Raif S Geha

doi:10.1172/JCI0214858

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Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations

Journal article

Open access

Peer reviewed

Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations

Jordan S Orange, Scott R Brodeur, Ashish Jain, Francisco A Bonilla, Lynda C Schneider, Roberto Kretschmer, Samuel Nurko, Wendy L Rasmussen, Julia R Köhler, Stephen E Gellis, …

The Journal of clinical investigation, Vol.109(11), pp.1501-1509

06/2002

DOI: 10.1172/JCI0214858

PMCID: PMC150995

PMID: 12045264

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Abstract

NF-kappaB essential modifier (NEMO), also known as IKK-gamma, is a member of the I-kappaB kinase complex responsible for phosphorylating I-kappaB, allowing the release and activation of NF-kappaB. Boys with an expressed NEMO mutation have an X-linked syndrome characterized by hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID). The immunophenotype resulting from NEMO mutation is highly variable, with deficits in both T and B cell responses. We evaluated three patients with NEMO mutations (L153R, Q403X, and C417R) and HED-ID who had evidence of defective CD40 signaling. All three patients had normal percentages of peripheral blood NK cells, but impaired NK cell cytotoxic activity. This was not due to a generalized defect in cytotoxicity because antibody-dependent cellular cytotoxicity was intact. This abnormality was partially reversed by in vitro addition of IL-2, which was also able to induce NF-kappaB activation. In one patient with recurrent cytomegalovirus infections, administration of IL-2 partially corrected the NK cell killing deficit. These data suggest that NEMO participates in signaling pathways leading to NK cell cytotoxicity and that IL-2 can activate NF-kappaB and partially overcome the NK cell defect in patients with NEMO mutations.

Interleukin-2 - metabolism

Amino Acid Sequence

Up-Regulation

Hypohidrosis - genetics

Phosphorylation

Protein-Serine-Threonine Kinases - physiology

Humans

Ectodermal Dysplasia - enzymology

Protein-Serine-Threonine Kinases - genetics

Child, Preschool

Molecular Sequence Data

Immunophenotyping

Infant

Male

NF-kappa B - metabolism

I-kappa B Kinase

CD40 Antigens - biosynthesis

Time Factors

Adolescent

Ectodermal Dysplasia - genetics

Models, Genetic

Killer Cells, Natural - metabolism

Mutation

Hypohidrosis - enzymology

Details

Title: Subtitle: Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations
Creators: Jordan S Orange - Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
Scott R Brodeur
Ashish Jain
Francisco A Bonilla
Lynda C Schneider
Roberto Kretschmer
Samuel Nurko
Wendy L Rasmussen
Julia R Köhler
Stephen E Gellis
Betsy M Ferguson
Jack L Strominger
Jonathan Zonana
Narayanaswamy Ramesh
Zuhair K Ballas
Raif S Geha
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.109(11), pp.1501-1509
DOI: 10.1172/JCI0214858
PMID: 12045264
PMCID: PMC150995
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Grant note: AI-31136 / NIAID NIH HHS\nR01 DE011311 / NIDCR NIH HHS\nM01 RR002172 / NCRR NIH HHS\nM01-RR02172 / NCRR NIH HHS\nT32 AI007512 / NIAID NIH HHS\nU19 AI031541 / NIAID NIH HHS\nR01 AI031136 / NIAID NIH HHS\nAI-31541 / NIAID NIH HHS\nAI-07512 / NIAID NIH HHS\nDE-11311 / NIDCR NIH HHS\nP01 AI031541 / NIAID NIH HHS
Language: English
Date published: 06/2002
Academic Unit: Immunology; Internal Medicine
Record Identifier: 9984094637602771

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