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.
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.
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.
The loss of the NEMO ZF-domain and almost complete persistence of CD4+CD45RA+ naïve T-cells despite severe infections is predictive for a profound innate and adaptive immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.