T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency

J Clin Immunol. 2020 Apr;40(3):421-434. doi: 10.1007/s10875-019-00728-y. Epub 2020 Jan 21.


Purpose: NEMO-deficient patients present with variable degrees of immunodeficiency. Accordingly, treatment ranges from antibiotic prophylaxis and/or IgG-substitution to allogenic hematopoietic stem cell transplantation (HSCT). The correct estimation of the immunodeficiency is essential to avoid over- as well as under-treatment. We compare the immunological phenotype of a NEMO-deficient patient with a newly-described splice site mutation that causes truncation of the NEMO zinc-finger (ZF) domain and a severe clinical course with the immunological phenotype of three NEMO-deficient patients with missense mutations and milder clinical courses and all previously published patients.

Methods: Lymphocyte subsets, proliferation, and intracellular NEMO-expression were assessed by FACS. NF-κB signal transduction was determined by measuring IκBα-degradation and the production of cytokines upon stimulation with TNF-α, IL-1β, and TLR-agonists in immortalized fibroblasts and whole blood, respectively.

Results: The patient with truncated ZF-domain of NEMO showed low levels of IgM and IgG, reduced class-switched memory B cells, almost complete skewing towards naïve CD45RA+ T cells, impaired T cell proliferation as well as cytokine production upon stimulation with TNF-α, IL-1β, and TLR-agonists. He suffered from severe infections (sepsis, pneumonia, osteomyelitis) during infancy. In contrast, three patients with missense mutations in IKBKG presented neither skewing of T cells towards naïvety nor impaired T cell proliferation. They are stable on prophylactic IgG-substitution or even off any prophylactic treatment.

Conclusion: The loss of the ZF-domain and the impaired T cell proliferation accompanied by almost complete persistence of naïve T cells despite severe infections are suggestive for a profound immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.

Keywords: CD45RA+ naïve T cells; NEMO deficiency; Primary immunodeficiency; T cell deficiency; immunological phenotype.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Proliferation
  • Cells, Cultured
  • Child, Preschool
  • Female
  • Genotype*
  • Humans
  • I-kappa B Kinase / genetics*
  • Immunoglobulin G / metabolism
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology*
  • Immunologic Memory
  • Infant
  • Male
  • Pedigree
  • Phenotype
  • Prognosis
  • Sequence Deletion / genetics*
  • T-Lymphocytes / immunology*


  • IKBKG protein, human
  • Immunoglobulin G
  • I-kappa B Kinase