Boast Brigette, Nunes-Santos Cristiane de Jesus, Kuehn Hye Sun, Rosenzweig Sergio D
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, United States.
Front Pediatr. 2021 Jul 16;9:705497. doi: 10.3389/fped.2021.705497. eCollection 2021.
The normal expression of Ikaros (IKZF1) is important for the proper functioning of both the human and murine immune systems. Whilst our understanding of IKZF1 in the immune system has been greatly enhanced by the study of mice carrying mutations in , analyses of human patients carrying germline mutations have been instrumental in understanding its biological role within the human immune system and its effect on human disease. A myriad of different mutations in have been identified, spanning across the entire gene causing differential clinical outcomes in patients including immunodeficiency, immune dysregulation, and cancer. The majority of mutations in humans leading to IKAROS-associated diseases are single amino acid heterozygous substitutions that affect the overall function of the protein. The majority of mutations studied in mice however, affect the expression of the protein rather than its function. Murine studies would suggest that the complete absence of IKZF1 expression leads to severe and sometimes catastrophic outcomes, yet these extreme phenotypes are not commonly observed in patients carrying heterozygous mutations. It is unknown whether this discrepancy is simply due to differences in zygosity, the role and regulation of IKZF1 in the murine and human immune systems, or simply due to a lack of similar controls across both groups. This review will focus its analysis on the current literature surrounding what is known about germline IKZF1 defects in both the human and the murine immune systems, and whether existing mice models are indeed accurate tools to study the effects of IKZF1-associated diseases.
Ikaros（IKZF1）的正常表达对于人类和小鼠免疫系统的正常运作都很重要。虽然通过对携带IKZF1突变的小鼠的研究，我们对其在免疫系统中的理解有了很大提高，但对携带种系IKZF1突变的人类患者的分析，对于理解其在人类免疫系统中的生物学作用及其对人类疾病的影响起到了重要作用。已鉴定出IKZF1中无数种不同的突变，这些突变遍布整个基因，导致患者出现不同的临床结果，包括免疫缺陷、免疫失调和癌症。在人类中，导致IKAROS相关疾病的大多数突变是影响蛋白质整体功能的单氨基酸杂合替代。然而，在小鼠中研究的大多数突变影响的是蛋白质的表达而非其功能。小鼠研究表明，IKZF1表达完全缺失会导致严重甚至灾难性的后果，但在携带IKZF1杂合突变的患者中并不常见这种极端表型。尚不清楚这种差异是仅仅由于杂合性的差异、IKZF1在小鼠和人类免疫系统中的作用及调控，还是仅仅由于两组缺乏相似的对照。本综述将集中分析当前围绕人类和小鼠免疫系统中种系IKZF1缺陷的已知情况的文献，以及现有的小鼠模型是否确实是研究IKZF1相关疾病影响的准确工具。
