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.

中文翻译：

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T 细胞受损可预测 NEMO 缺乏症的严重临床过程。

目的 NEMO 缺陷患者表现为不同程度的免疫缺陷。因此，治疗范围从抗生素预防和/或 IgG 替代到同种异体造血干细胞移植 (HSCT)。正确估计免疫缺陷对于避免过度治疗和治疗不足至关重要。我们将 NEMO 缺陷患者的免疫表型与新描述的导致 NEMO 锌指 (ZF) 结构域截断的剪接位点突变和严重的临床病程与三名具有错义突变的 NEMO 缺陷患者的免疫表型进行比较和温和的临床过程和所有以前发表的患者。方法通过 FACS 评估淋巴细胞亚群、增殖和细胞内 NEMO 表达。通过测量永生化成纤维细胞和全血中分别用 TNF-α、IL-1β 和 TLR 激动剂刺激后的 IκBα 降解和细胞因子的产生来确定 NF-κB 信号转导。结果 NEMO ZF 结构域截短的患者表现出低水平的 IgM 和 IgG，减少类别转换记忆 B 细胞，几乎完全向幼稚 CD45RA+ T 细胞倾斜，T 细胞增殖受损以及在用 TNF-α 刺激后产生细胞因子、IL-1β 和 TLR 激动剂。他在婴儿时期遭受严重感染（败血症、肺炎、骨髓炎）。相比之下，三名 IKBKG 错义突变的患者既没有表现出 T 细胞向幼稚的倾斜，也没有出现 T 细胞增殖受损。它们对预防性 IgG 替代或什至在任何预防性治疗中都是稳定的。结论 ZF 结构域的丧失和 T 细胞增殖受损，伴随着尽管严重感染的幼稚 T 细胞几乎完全持续存在，表明存在严重的免疫缺陷。在出现慢性后遗症之前，应尽早考虑对这些患者进行异基因造血干细胞移植。