Novel NF-kappa B Inhibitor Alpha Gain-of-Function Variant in an Infant with Lymphocytosis and Recurrent Serratia Bacteremia.
Novel NF-kappa B Inhibitor Alpha Gain-of-Function Variant in an Infant with Lymphocytosis and Recurrent Serratia Bacteremia.
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新型 NF-kappa B 抑制剂 Alpha 功能获得变体治疗患有淋巴细胞增多症和复发性沙雷氏菌血症的婴儿。
DOI：
10.1007/s10875-023-01481-z
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发表时间：
2023
影响因子：
9.1
通讯作者：
Khojah,Amer
中科院分区：
文献类型：
--
作者：
Gunderman,LaurenM;Asano,Takaki;Casanova,Jean-Laurent;Boisson,Bertrand;Khojah,Amer
核因子-κ B（NF-κB）通路的激活对于淋巴细胞存活和正常免疫功能至关重要。NF-κB由5个成员（NF KB 1、NF KB 2、RELA、RELB和c-REL）组成，并且作为转录因子，其在先天性和适应性免疫应答的激活中起关键的调节作用。抑制性NF-κB蛋白（IκB）家族由IκBα、IκBβ和IκBε三个亚基组成，它们将NF-κB保留在细胞质中。一旦Iκ B被磷酸化，它们就会被蛋白酶体泛素化并降解。IκB降解后，NF-κ B易位至细胞核进行基因转录[1]。NF-κB信号传导有多种激活剂，包括感染因子、辐射诱导的双链DNA断裂和促炎细胞因子，如肿瘤坏死因子（TNF）和白细胞介素1（IL-1），通过激活其各自的受体[1，2]。由于激活剂种类繁多，该途径的缺陷导致广泛的感染倾向[3]。NF κ BIA编码IκBα，当过度激活时，通过限制转录因子易位到细胞核进行基因转录的能力，导致NF-κB的持续抑制。结果是常染色体显性遗传性无汗性外胚层发育不良伴免疫缺陷（EDA-ID），这是一种由NF-κB通路失败导致的联合免疫缺陷，导致T细胞免疫缺陷、B细胞功能差和外胚层发育不良的不同严重程度[3]。在这封信中，我们描述了一个病人谁出生后不久，复发性感染，淋巴细胞增多症，先天性异常，并被发现有一个新的，私人NF-κ B抑制剂α（NFKBIA）变异，其特征是在体外获得功能（GOF）等位基因。在进行造血干细胞移植（HSCT）之前，通过成纤维细胞培养证实了该等位基因的显性效应。患者是一名32周前出生的男婴，父母均为健康非血缘关系，有宫内生长受限（IUGR）和羊水过少病史。他是通过紧急剖腹产出生的臀位和不放心胎心音。分娩时，患者出现弥漫性皮疹和血小板减少症。发现多种先天性异常，包括小颌畸形和耳杯，成像显示双侧13根肋骨（副肋骨）和心脏钙化。脑MRI显示脑软化，推测为产前起源。尽管在新生儿筛查中TREC计数正常，但在7周龄时，他已接受了复发性甲氧西林敏感性葡萄球菌的治疗。
Activation of the Nuclear Factor-kappa B (NF-κB) pathway is essential for lymphocyte survival and normal immune functioning. NF-κB is constituted of 5 members (NFKB1, NFKB2, RELA, RELB, and c-REL), and as a transcription factor, it plays a crucial regulatory role in the activation of both innate and adaptive immune responses. The inhibitory NF-κB protein (IκB) family consists of three subunits, IκBα, IκBβ and IκBε, which retain NF-κB in the cytoplasm. Once IκBs are phosphorylated, they are ubiquitinated and degraded by the proteasome. Following IκB degradation, NF-κBs are translocated to the nucleus for gene transcription [1]. There are multiple activators of NF-κB signaling including infectious agents, radiation-induced double stranded DNA breaks, and proinflammatory cytokines such as tumor necrosis factor (TNF) and Interleukin 1 (IL-1) through the activation of their respective receptors [1, 2]. Given the wide array of activators, deficiencies in this pathway lead to an extensive predisposition to infection [3]. NFKBIA encodes IκBα which, when over activated, leads to persistent inhibition of NF-κB by restricting the transcription factor’s ability to translocate to the nucleus for gene transcription. The outcome is autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), a combined immunodeficiency resulting from failure of the NF-κB pathway leading to T cell immunodeficiency, poor B cell function, and varying severity of ectodermal dysplasia [3]. In this letter, we describe a patient who presented shortly after birth with recurrent infections, lymphocytosis, and congenital anomalies and was found to have a novel, private NF-kappa B Inhibitor Alpha (NFKBIA) variant, characterized in vitro to be a gain-of-function (GOF) allele. Confirmation of the dominant effect of this allele was completed using a fibroblast culture prior to pursuit of hematopoietic stem cell transplant (HSCT).The patient is an ex-32-week-old male infant, born to healthy nonconsanguineous parents, with a history of intrauterine growth restriction (IUGR) and oligohydramnios. He was born via emergency cesarean section for breech presentation and non-reassuring fetal heart tones. At delivery, he had a diffuse erythematous papular rash and thrombocytopenia. Multiple congenital abnormalities were noted including micrognathia and ear cupping with imaging showing 13 ribs bilaterally (accessory ribs) and cardiac calcifications. Brain MRI revealed encephalomalacia, assumed to be antenatal in origin. Despite normal TREC counts on the newborn screen, by 7 weeks of age, he had been treated for recurrent methicillin-susceptible Staphylo-