Hoshino Akihiro, Boutboul David, Zhang Yuan, Kuehn Hye Sun, Hadjadj Jerôme, Özdemir Nihal, Celkan Tiraje, Walz Christoph, Picard Capucine, Lenoir Christelle, Mahlaoui Nizar, Klein Christoph, Peng Xiao, Azar Antoine, Reigh Erin, Cheminant Morgane, Fischer Alain, Rieux-Laucat Frédéric, Callebaut Isabelle, Hauck Fabian, Milner Joshua, Rosenzweig Sergio D, Latour Sylvain
Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France.
Department of Pediatrics, Irving Medical Center, Columbia University, New York, NY, USA.
Sci Immunol. 2022 Mar 25;7(69):eabi7160. doi: 10.1126/sciimmunol.abi7160.
IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline haploinsufficient () and dominant-negative () variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T) skewing toward T2, low numbers of regulatory T cells (T), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1 and IKZF1, IKZF1 proteins showed increased DNA binding associated with increased gene expression of T2 and PC differentiation, thus demonstrating that behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T2 and PC abnormalities caused by IKZF1. These data extend the spectrum of pathological mechanisms associated with deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.
IKZF1/IKAROS是淋巴细胞发育过程中的关键转录因子，在整个造血过程中均有表达。人类中的杂合种系单倍体不足（）和显性负性（）变体可导致B细胞免疫缺陷和联合免疫缺陷。在此，我们在8名有炎症、自身免疫、过敏症状以及浆细胞（PC）增殖异常的个体中，鉴定出位于DNA结合域的先前未被识别的杂合变体（R183C/H）。患者的白细胞表现出特定缺陷，包括T细胞产生IL-2受损、T辅助细胞（Th）向Th2偏移、调节性T细胞（Treg）数量减少、嗜酸性粒细胞增多以及PC增殖异常。与IKZF1和IKZF1不同，IKZF1蛋白显示出与Th2和PC分化基因表达增加相关的DNA结合增加，从而表明其表现为功能获得性（GOF）等位基因。用已知可降解IKZF1的来那度胺进行体外处理，纠正了由IKZF1引起的Th2和PC异常。这些数据扩展了与IKZF1缺陷相关的病理机制谱，并突出了IKZF1在晚期淋巴细胞分化阶段的作用。
