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

IKBKG (nuclear factor-κB essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function

“…9 TLR ligandinduced TNF responses were measured by ELISA 24 hours after stimulation as described. 7 NK cell cytotoxicity against K562 erythroleukemia target cells was measured by using 51Cr-release assay according to previously published methods 10 with PBMCs obtained during periods of relative wellness and >6 months after the initial presentation.…”

“…Cytomegalovirus infection has been previously reported in patients with a NEMO mutation. 6,10 Although atypical susceptibility to and unusual consequences of cytomegalovirus infection can be associated with T-cell impairment, appropriate defense against cytomegalovirus also requires NK cell function. 15 Because deficiencies of NK cells have been identified in patients with a NEMO mutation, 5,10 NK cell cytotoxicity was assessed to determine whether a deficiency in NK cell defenses could have contributed to his infectious phenotype.…”

NF-κB and the regulation of hematopoiesis

“…In three patients, the number of circulating NK cells was unaffected but the cytotoxic activity of these cells was impaired. 53 …”

NF-κB-related genetic diseases

“…37 In contrast, patients with EDA-ID have a normal T-cell proliferation index in response to mitogens and antigens.…”