Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB–inducing kinase and impairs lymphotoxin-β–driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKα^Y580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVβ repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.

中文翻译：

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由核因子 𝛋B 激酶 α (IKKα) 抑制剂的纯合错义突变引起的联合免疫缺陷和自身免疫

核因子 kappa B 激酶 α (IKKα) 的抑制剂对于 p100/NF-κB2 磷酸化和加工成 p52 以及非经典 NF-κB 通路的激活至关重要。一名患有反复感染、骨骼异常、二级淋巴结构缺失、B 细胞数量减少、低丙种球蛋白血症以及肠和肝淋巴细胞浸润的患者被发现在 IKKα 的螺旋-环-螺旋结构域中具有纯合 p.Y580C 突变。该突变保留了 IKKα 激酶活性，但消除了 IKKα 与其激活因子 NF-κB 诱导激酶的相互作用，并损害了淋巴毒素-β 驱动的 p100/NF-κB2 加工和VCAM1表达。纯合 IKKα ^Y580C/Y580C突变小鼠对患者的发现进行表型检查；缺乏边缘区 B 细胞、生发中心和抗原特异性 T 细胞对皮肤免疫的反应；Il17a表达受损；并且易感染皮肤金黄色葡萄球菌。此外，这些小鼠表现出髓质胸腺上皮细胞严重减少、胸腺细胞负选择受损、TCRVβ库受限、潜在自身反应性 T 细胞克隆的选择性扩增、调节性 T 细胞频率降低以及肝脏、胰腺浸润，与器官损伤同时发生的活化 T 细胞和肺。因此，本研究将 IKKα 缺乏确定为先前未描述的与相关自身免疫相关的原发性免疫缺陷的原因。