Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Vanderbilt University School of Medicine, Nashville, TN, USA.
J Clin Immunol. 2022 Nov;42(8):1583-1592. doi: 10.1007/s10875-022-01327-0. Epub 2022 Jul 22.
Cells of the innate and adaptive immune systems depend on proper actin dynamics to control cell behavior for effective immune responses. Dysregulated actin networks are known to play a pathogenic role in an increasing number of inborn errors of immunity. The WAVE regulatory complex (WRC) mediates branched actin polymerization, a process required for key cellular functions including migration, phagocytosis, vesicular transport, and immune synapse formation. Recent reports of pathogenic variants in NCKAP1L, a hematopoietically restricted gene encoding the HEM1 protein component of the WRC, defined a novel disease involving recurrent bacterial and viral infections, autoimmunity, and excessive inflammation (OMIM 141180). This review summarizes the diverse clinical presentations and immunological phenotypes observed in HEM1-deficient patients. In addition, we integrate the pathophysiological mechanisms described in current literature and highlight the outstanding questions for diagnosis and management of the HEM1 actin immunodysregulatory disorder.
先天和适应性免疫系统的细胞依赖于适当的肌动蛋白动力学来控制细胞行为，以实现有效的免疫反应。越来越多的先天性免疫缺陷被认为是肌动蛋白网络失调发挥致病作用的结果。WAVE 调节复合物 (WRC) 介导分支肌动蛋白聚合，这是包括迁移、吞噬作用、囊泡运输和免疫突触形成在内的关键细胞功能所必需的过程。最近报道的造血受限基因 NCKAP1L 中的致病性变异体，该基因编码 WRC 的 HEM1 蛋白成分，定义了一种涉及复发性细菌和病毒感染、自身免疫和过度炎症的新疾病（OMIM 141180）。本综述总结了 HEM1 缺陷患者观察到的不同临床表现和免疫学表型。此外，我们整合了当前文献中描述的病理生理学机制，并强调了诊断和管理 HEM1 肌动蛋白免疫调节紊乱的待解决问题。
