Nuffield Department of Medicine and National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Clinical Immunology Department, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Clin Immunol. 2022 Jan;234:108910. doi: 10.1016/j.clim.2021.108910. Epub 2021 Dec 15.
Genetic variants in PIK3CD, PIK3R1 and NFKB1 cause the primary immune deficiencies, activated PI3Kδ syndrome (APDS) 1, APDS2 and NFκB1 haploinsufficiency, respectively. We have identified a family with known or potentially pathogenic variants NFKB1, TNFRSF13B and PIK3R1. The study's aim was to describe their associated immune and cellular phenotypes and compare with individuals with monogenic disease. NFκB1 pathway function was measured by immunoblotting and PI3Kδ pathway activity by phospho-flow cytometry. p105/p50 expression was absent in two individuals but elevated pS6 only in the index case. Transfection of primary T cells demonstrated increased basal pS6 signalling due to mutant PIK3R1, but not mutant NFKB1 or their wildtype forms. We report on the presence of pathogenic variant NFKB1, with likely modifying variants in TNFRSF13B and PIK3R1 in a family. We describe immune features of both NFκB1 haploinsufficiency and APDS2, and the inhibition of excessive PI3K signalling by rapamycin in vitro.
PIK3CD、PIK3R1 和 NFKB1 的遗传变异分别导致原发性免疫缺陷、激活的 PI3Kδ 综合征（APDS）1、APDS2 和 NFKB1 单倍不足。我们已经鉴定出一个具有已知或潜在致病性变异的 NFKB1、TNFRSF13B 和 PIK3R1 的家族。该研究的目的是描述它们相关的免疫和细胞表型，并与单基因疾病患者进行比较。通过免疫印迹测量 NFκB1 途径的功能，通过磷酸化流式细胞术测量 PI3Kδ 途径的活性。两个人的 p105/p50 表达缺失，但仅在索引病例中 pS6 升高。原代 T 细胞的转染表明，由于突变型 PIK3R1，基础 pS6 信号增加，但突变型 NFKB1 或其野生型形式则不然。我们报告了一个家族中存在致病性变异的 NFKB1，以及 TNFRSF13B 和 PIK3R1 中可能存在的修饰变异。我们描述了 NFκB1 单倍不足和 APDS2 的免疫特征，以及体外雷帕霉素对过度 PI3K 信号的抑制作用。
