Abstract
The gene that encodes nuclear factor κ (NF-κB) essential modulator (or NEMO, also known as IKKγ) is required for activation of the transcription factor NF-κB. We describe mutations in the puta-tive zinc-finger domain of NEMO that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED). These mutations prevent CD40 ligand (CD40L)-mediated degradation of inhibitor of NF-κB α (IκB-α) and account for the following observations: B cells from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and antigen-presenting cells (APCs) are unable to synthesize the NF-κB–regulated cytokines interleukin 12 (IL-12) or tumor necrosis factor α (TNF-α) when stimulated with CD40L. Nevertheless, innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan's antigen (SAC). Overall, the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40-mediated NF-κB activation for B cell immunoglobulin class-switching.
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Acknowledgements
We thank the families studied for their invaluable contribution to this project; R. Dhanasekaran for technical assistance; V. Dixit (Genentech), J. Derry and W. Fanslow (Immunex), P. Lipsky, A. Grammer and K. Brown for helpful discussions; and U. Seibenlist for critical review of the manuscript. Supported by the Immune Deficiency Foundation and the National Foundation of Ectodermal Dysplasia
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Jain, A., Ma, C., Liu, S. et al. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2, 223–228 (2001). https://doi.org/10.1038/85277
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DOI: https://doi.org/10.1038/85277
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