title: Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations.
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.
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Scott R
authors.initials: SR
authors.lastname: Brodeur
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Bonilla
authors.forename: Lynda C
authors.initials: LC
authors.lastname: Schneider
authors.forename: Roberto
authors.initials: R
authors.lastname: Kretschmer
authors.forename: Samuel
authors.initials: S
authors.lastname: Nurko
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Rasmussen
authors.forename: Julia R
authors.initials: JR
authors.lastname: Köhler
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gellis
authors.forename: Betsy M
authors.initials: BM
authors.lastname: Ferguson
authors.forename: Jack L
authors.initials: JL
authors.lastname: Strominger
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zonana
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Ramesh
authors.forename: Zuhair K
authors.initials: ZK
authors.lastname: Ballas
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019013:CD40 Antigens / Q000096:biosynthesis; D002675:Child, Preschool; D004476:Ectodermal Dysplasia / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007007:Hypohidrosis / Q000201:enzymology* / Q000235:genetics*; D051550:I-kappa B Kinase; D016130:Immunophenotyping; D007223:Infant; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D019013:CD40 Antigens; D007376:Interleukin-2; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human