先天性免疫错误(IEI)是人类的一组疾病,通常表现为对感染的易感性增加,自身免疫,炎症过度,过敏,在某些情况下是恶性肿瘤。在与IEI相关的新鉴定的基因中,包括来自7个独立家族的9个个体的3个独立报告,这些个体患有严重的原发性免疫缺陷病(PID)和自身免疫,这是由于编码造血蛋白1(HEM1)的NCKAP1L基因的功能丧失突变所致。HEM1是WASp家族Verprolin同源(WAVE)调节复合物(WRC)的造血细胞特异性成分,它在多个免疫受体的下游起作用以刺激肌动蛋白成核和丝状肌动蛋白(F-actin)的聚合。F-肌动蛋白的聚合和分支对于创建产生力的细胞骨架结构至关重要,这些结构驱动大多数活跃的细胞过程,包括迁移。附着力,免疫突触形成,和吞噬作用。细胞皮质处的分支肌动蛋白网络也涉及作为屏障来调节不适当的囊泡(例如细胞因子)分泌和自发抗原受体交联。鉴于肌动蛋白细胞骨架在大多数或所有造血细胞中的重要性,HEM1缺陷患儿表现出复杂的临床表现,包括免疫缺陷和自身免疫的重叠特征,这并不奇怪.在这次审查中,我们将概述HEM1和WRC在免疫和其他细胞中的分子和细胞功能。我们将描述人类HEM1缺乏症的常见临床病理特征和免疫表型,并使用组成型和免疫细胞特异性小鼠敲除模型提供有关Hem1破坏的详细比较描述。最后,我们讨论了关于HEM1和WRC的未来观点和重要调查领域。
Inborn errors of immunity (IEI) are a group of diseases in humans that typically present as increased susceptibility to infections, autoimmunity, hyperinflammation, allergy, and in some cases malignancy. Among newly identified genes linked to IEIs include 3 independent reports of 9 individuals from 7 independent kindreds with severe primary immunodeficiency disease (PID) and autoimmunity due to loss-of-function mutations in the NCKAP1L gene encoding Hematopoietic protein 1 (HEM1). HEM1 is a hematopoietic cell specific component of the WASp family verprolin homologous (WAVE) regulatory complex (WRC), which acts downstream of multiple immune receptors to stimulate actin nucleation and polymerization of filamentous actin (F-actin). The polymerization and branching of F-actin is critical for creating force-generating cytoskeletal structures which drive most active cellular processes including migration, adhesion, immune synapse formation, and phagocytosis. Branched actin networks at the cell cortex have also been implicated in acting as a barrier to regulate inappropriate vesicle (e.g. cytokine) secretion and spontaneous antigen receptor crosslinking. Given the importance of the actin cytoskeleton in most or all hematopoietic cells, it is not surprising that HEM1 deficient children present with a complex clinical picture that involves overlapping features of immunodeficiency and autoimmunity. In this review, we will provide an overview of what is known about the molecular and cellular functions of HEM1 and the WRC in immune and other cells. We will describe the common clinicopathological features and immunophenotypes of HEM1 deficiency in humans and provide detailed comparative descriptions of what has been learned about Hem1 disruption using constitutive and immune cell-specific mouse knockout models. Finally, we discuss future perspectives and important areas for investigation regarding HEM1 and the WRC.