Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 122, Issue 6, Pages 1169-1177Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2008.08.018
Keywords
NEMO; immunodeficiency; genetic database; Jurkat reconstitution; NF-kappa B activation; A20
Categories
Funding
- National Institutes of Health (NIH) [AI079731, HL080612, 5T32CA009140-33]
- US Immnodeficiency Network [NIH N01 AI-22070]
- Pennsylvania Department of Health
- American Academy of Allergy. Asthma Immunology
- Penn Center for Clinical Immunology Jackson-Wade Fellowship
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Background: Human hypomorphic nuclear factor-kappa B essential modulator (NEMO) mutations cause diverse clinical and immunologic phenotypes, but understanding of their scope and mechanistic links to immune function and genotype is incomplete. Objective: We created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights. Methods: Phenotypes of 72 individuals with NEMO mutations were compiled. NEMO L153R and C417R were investigated further in a reconstitution system. TNF-alpha or Toll-like receptor (TLR)-5 signals were evaluated for nuclear factor-kappa B activation, programmed cell death, and A20 gene expression. Results: Thirty-two different mutations were identified; 53% affect the zinc finger domain. Seventy-seven percent were associated with ectodermal dysplasia, 86% with serious pyogenic infection, 39% with mycobacterial infection, 19% with serious viral infection, and 23% with inflammatory diseases. Thirty-six percent of individuals died at a mean age of 6.4 years. CD40, IL-1, TNF-alpha, TLR, and T-cell receptor signals were impaired in 15 of 16 (94%), 6 of 7 (86%), 9 of 11 (82%), 9 of 14 (64%), and 7 of 18 (39%), respectively. Hypomorphism-reconstituted NEMO-deficient cells demonstrated partial restoration of NEMO functions. Although both L153R and C417R impaired TLR and TNF-alpha-induced NF-kappa B activation, L153R also increased TNF-alpha-induced programmed cell death with decreased A20 expression. Conclusion: Distinct NEMO hypomorphs define specific disease and genetic characteristics. A reconstitution system can identify attributes of hypomorphisms independent of an individual's genetic background. Apoptosis susceptibility in L153R reconstituted cells defines a specific phenotype of this mutation that likely contributes to the excessive inflammation with which it is clinically associated. (J Allergy Clin Immunol 2008; 122:1169-77.)
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