IRF2BP2 Deficiency: An important form of common variable immunodeficiency with inflammation.

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology Pub Date : 2025-03-14 DOI:10.1016/j.jaci.2025.02.038

Chioma Udemgba, Bethany Pillay, Samantha Shafer, Angelika Alberstadt, Michael Abers, Olivier Gilliaux, Karin Chen, William Rae, Leif Hanitsch, Horst Von Bernuth, Joao Farela Neves, Nikita Raje, Leen Moens, P Martin van Hagen, Jenna Bergerson, Nicholas Hartog, Tim Niehues, Gregor Dückers, Emilia Falcone, Michael Keller, Amy Hsu, Isabelle Meyts, Steven M Holland

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引用次数: 0

Abstract

Background: Interferon regulatory factor-2 binding protein-2 (IRF2BP2) is a transcription factor that plays an important role in regulating immune pathways, angiogenesis, apoptosis, and cell differentiation. Defects in this gene have been implicated in immunodeficiency.

Objective: To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test thirty-four individuals with IRF2BP2 variants.

Methods: We collected 34 subjects across 18 families with mutations in IRF2BP2. Records were abstracted for clinical phenotypes. Functional testing was performed on peripheral blood mononuclear cells (PBMCs). Nuclear factor of activated T cells (NFAT) luciferase gene reporter constructs and quantitative cDNA determinations were used to evaluate repressor activity associated with ectopic expression of various IRF2BP2 mutant constructs in Jurkat cells.

Results: Most subjects had immunodeficiency (91%, n = 30/33) with variable gastrointestinal (65%, n= 20/31) and inflammatory or autoimmune features (57%, n=17/30), including chronic abdominal pain, colitis, diarrhea, constipation, vitiligo, alopecia, and migratory rashes. There was a reduced frequency of memory B-cells with poor immunoglobulin production and reduced calcium flux in response to B-cell receptor stimuli. PBMCs had increased apoptosis in vitro compared to healthy controls. Impaired IRF2BP2 repression of NFAT activation was observed using patient-derived mutant IRF2BP2 constructs compared to wild-type. Similarly, TNF-α transcript levels were higher using patient-derived mutations compared to wild-type IRF2BP2 constructs.

Conclusions: IRF2BP2 deficiency causes a complex immunodeficiency including gastrointestinal and inflammatory disorders as well as impaired B-cell maturation. Impaired repression of the NFAT pathway appears to enhance proinflammatory signaling through proinflammatory cytokine expression.

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IRF2BP2缺陷：常见变异性免疫缺陷伴炎症的一种重要形式。

背景：干扰素调节因子-2结合蛋白-2 （IRF2BP2）是一种在调节免疫途径、血管生成、细胞凋亡和细胞分化等方面发挥重要作用的转录因子。这种基因的缺陷与免疫缺陷有关。目的：为了加深对IRF2BP2变异的临床意义的理解，我们试图对34名IRF2BP2变异个体进行临床表征和功能检测。方法：我们收集了来自18个IRF2BP2突变家族的34名受试者。提取临床表型记录。外周血单个核细胞（PBMCs）功能检测。利用活化T细胞核因子（NFAT）荧光素酶基因报告基因构建体和定量cDNA测定来评估Jurkat细胞中各种IRF2BP2突变构建体异位表达相关的抑制因子活性。结果：大多数受试者具有免疫缺陷（91%,n= 30/33），并伴有胃肠道（65%,n= 20/31）和炎症或自身免疫特征（57%,n=17/30），包括慢性腹痛、结肠炎、腹泻、便秘、白癜风、脱发和迁移性皮疹。在b细胞受体刺激下，记忆性b细胞的频率降低，免疫球蛋白产生不良，钙通量减少。与健康对照组相比，pbmc体外细胞凋亡增加。与野生型相比，使用患者衍生的突变型IRF2BP2结构观察到IRF2BP2对NFAT激活的抑制受损。同样，与野生型IRF2BP2构建体相比，患者衍生突变的TNF-α转录水平更高。结论：IRF2BP2缺乏导致复杂的免疫缺陷，包括胃肠道和炎症性疾病以及b细胞成熟受损。NFAT通路的抑制受损似乎通过促炎细胞因子的表达增强促炎信号。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Allergy and Clinical Immunology 医学-过敏

CiteScore

25.90

自引率

7.70%

发文量

1302

审稿时长

38 days

期刊介绍： The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.