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

被引:162
作者
Orange, JS
Brodeur, SR
Jain, A
Bonilla, FA
Schneider, LC
Kretschmer, R
Nurko, S
Rasmussen, WL
Köhler, JR
Gellis, SE
Ferguson, BM
Strominger, JL
Zonana, J
Ramesh, N
Ballas, ZK
Geha, RS
机构
[1] Childrens Hosp, Div Immunol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA USA
[3] NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA
[4] Hosp ABC, Dept Pediat, Mexico City, DF, Mexico
[5] Iowa City Vet Adm, Dept Internal Med, Iowa City, IA USA
[6] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
[7] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
[8] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[9] Harvard Univ, Dept Cell & Mol Biol, Cambridge, MA 02138 USA
关键词
D O I
10.1172/JCI200214858
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 (L153, 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.
引用
收藏
页码:1501 / 1509
页数:9
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