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Heller, Stephanie; Koelsch, Uwe; Magg, Thomas; Krueger, Renate; Scheuern, Andrea; Schneider, Holm; Eichinger, Anna; Wahn, Volker; Unterwalder, Nadine; Lorenz, Myriam; Schwarz, Klaus; Meisel, Christian; Schulz, Ansgar; Hauck, Fabian; Bernuth, Horst von (2020): T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency. In: Journal of Clinical Immunology, Vol. 40, No. 3: pp. 421-434
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Abstract

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-kappa B signal transduction was determined by measuring I kappa B alpha-degradation and the production of cytokines upon stimulation with TNF-alpha, IL-1 beta, 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 naive CD45RA(+) T cells, impaired T cell proliferation as well as cytokine production upon stimulation with TNF-alpha, IL-1 beta, 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 naivety 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 naive T cells despite severe infections are suggestive for a profound immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.