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.
Functional Evaluation of an IKBKG Variant Suspected to Cause Immunodeficiency Without Ectodermal Dysplasia.J Clin Immunol. 2017 Nov;37(8):801-810. doi: 10.1007/s10875-017-0448-9. Epub 2017 Oct 10. J Clin Immunol. 2017. PMID: 28993958
Two-sided ubiquitin binding of NF-κB essential modulator (NEMO) zinc finger unveiled by a mutation associated with anhidrotic ectodermal dysplasia with immunodeficiency syndrome.J Biol Chem. 2013 Nov 22;288(47):33722-37. doi: 10.1074/jbc.M113.483305. Epub 2013 Oct 7. J Biol Chem. 2013. PMID: 24100029 Free PMC article.
Lack of interaction between NEMO and SHARPIN impairs linear ubiquitination and NF-κB activation and leads to incontinentia pigmenti.J Allergy Clin Immunol. 2017 Dec;140(6):1671-1682.e2. doi: 10.1016/j.jaci.2016.11.056. Epub 2017 Feb 27. J Allergy Clin Immunol. 2017. PMID: 28249776
EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation.Int Rev Immunol. 2015;34(6):445-59. doi: 10.3109/08830185.2015.1055331. Epub 2015 Aug 13. Int Rev Immunol. 2015. PMID: 26269396 Review.
Immunodeficiency.2019 Nov 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. StatPearls. 2020 Jan–. PMID: 29763203 Free Books & Documents. Review.