Deficient natural killer cell cytotoxicity in patients with IKK-γ/NEMO mutations
Jordan S. Orange, … , Zuhair K. Ballas, Raif S. Geha
Jordan S. Orange, … , Zuhair K. Ballas, Raif S. Geha
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1501-1509. https://doi.org/10.1172/JCI14858.
View: Text | PDF
Article Genetics

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

Abstract

NF-κB essential modifier (NEMO), also known as IKK-γ, is a member of the I-κB kinase complex responsible for phosphorylating I-κB, allowing the release and activation of NF-κB. 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-κB 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-κB and partially overcome the NK cell defect in patients with NEMO mutations.

Authors

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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Evaluation of nuclear NF-κB level in cells from a patient with NEMO exon...
Evaluation of nuclear NF-κB level in cells from a patient with NEMO exon 4 mutation (patient 1). Nuclear extracts of enriched B cells from patient 1 or a control donor were evaluated by EMSA using a 32P-labeled NF-κB probe. (a) The effect of CD40 ligation on the level of nuclear NF-κB was determined by incubation of enriched B cells with control medium or sCD40L for 30 minutes prior to cell lysis. (b) The ability of IL-2 to induce nuclear levels of NF-κB was assessed in PBMCs by stimulation with PHA for 18 hours, followed by resting for 5 hours and subsequent incubation with IL-2 or media for 5 hours prior to lysis. Nuclear extracts were prepared and evaluated for NF-κB binding. The arrow points to the retained NF-κB probe; the large band at the bottom of the gel corresponds to free probe.