Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα).
Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα).
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DOI：
10.1126/sciimmunol.abf6723
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发表时间：
2021-09-17
影响因子：
24.8
通讯作者：
Geha RS
中科院分区：
文献类型：
--
作者：
Bainter W;Lougaris V;Wallace JG;Badran Y;Hoyos-Bachiloglu R;Peters Z;Wilkie H;Das M;Janssen E;Beano A;Farhat KB;Kam C;Bercich L;Incardona P;Villanacci V;Bondioni MP;Meini A;Baronio M;Abarzua P;Parolini S;Tabellini G;Maio S;Schmidt B;Goldsmith JD;Murphy G;Hollander G;Plebani A;Chou J;Geha RS
核因子kappaB激酶α抑制物(ikkα)对p100/NF-κB2的磷酸化、P52的加工以及非规范的NF-κB通路的激活起着至关重要的作用。1例反复感染、骨骼异常、缺乏次级淋巴结构、B细胞数量减少、低丙种球蛋白血症、肠和肝脏淋巴细胞浸润的患者被发现在IKKα的螺旋-环状-螺旋结构域存在pY580C纯合子突变。该突变保留了IKKα激酶的活性，但取消了IKKα与其激活剂NF-κB诱导的激酶的相互作用，并损害了淋巴毒素β驱动的P100/NF-κB2的处理和VCAM1的表达。纯合子IKKαY580C/Y580C突变小鼠与患者的表现相似；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；以及对皮肤金黄色葡萄球菌感染敏感。此外，这些小鼠表现出髓质胸腺上皮细胞严重减少，胸腺细胞阴性选择受损，TCRVβ谱系受限，潜在的自身反应性T细胞克隆选择性扩增，调节性T细胞频率降低，以及与器官损伤同时激活的T细胞对肝、胰腺和肺的渗透。因此，这项研究确定IKKα缺陷是先前未描述的与自身免疫相关的原发免疫缺陷的原因。
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 IKKαY580C/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.
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影响因子：
32.4
作者：
Dejardin, E;Droin, NM;Green, DR
通讯作者：
Green, DR
上皮内膜IKKα表达调节3组先天淋巴样细胞反应和抗菌免疫。
DOI：
10.1084/jem.20141831
发表时间：
2015-09-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Giacomin PR;Moy RH;Noti M;Osborne LC;Siracusa MC;Alenghat T;Liu B;McCorkell KA;Troy AE;Rak GD;Hu Y;May MJ;Ma HL;Fouser LA;Sonnenberg GF;Artis D
通讯作者：
Artis D
影响因子：
11.4
作者：
Descargues, Pascal;Sil, Alok K.;Karin, Michael
通讯作者：
Karin, Michael
影响因子：
30.5
作者：
Aschenbrenner, Katharina;D'Cruz, Louise M.;Klein, Ludger
通讯作者：
Klein, Ludger
影响因子：
30.5
作者：
Claudio, E;Brown, K;Siebenlist, U
通讯作者：
Siebenlist, U