Körholz Julia, Tromp Samantha A M, Dalm Virgil A S H, de Bie Maaike, de Bree Godelieve J, van Leeuwen Ester M M, Fraaij Pieter L A, Jansen Machiel H, Hollink Iris H I M, Nagelkerke Sietse Q, Russ Susanne, Scholze Anne-Kathleen, Soomann Maarja, Wiedemuth Ralf, Pachlopnik Schmid Jana, Hanitsch Leif G, Schuetz Catharina, Kuijpers Taco W, IJspeert Hanna
Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Experimental Immunology, Amsterdam institute for Infection and Immunity, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Allergy Clin Immunol. 2025 Aug;156(2):279-293. doi: 10.1016/j.jaci.2025.04.033. Epub 2025 May 20.
The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway is a key regulator of immune responses, cell survival, and proliferation. Dysregulation of this signaling pathway is implicated in various human diseases, including inborn errors of immunity.
We describe the clinical heterogeneity in 16 patients from 4 unrelated families with missense variants in the kinase domain of IKK2 encoded by IKBKB.
Genetic variants (p.V203I and p.M65T) in the patients were identified by whole-exome sequencing. An NF-κB reporter assay was performed to investigate NF-κB activity. Extensive immunophenotyping, a lymphocyte proliferation assay, and signaling pathway analysis were performed to gain biological insight into the impact on B- and T-cell phenotype and function.
Whole-exome sequencing revealed 2 gain-of-function variants in the IKBKB gene, of which one was a novel variant. While lymphocyte cell numbers are generally normal at young ages, most adult patients exhibit strongly reduced B- and T-cell numbers. Although still normal in their proliferative capacity, B and T cells show defective activation at day 3 (CD70, CD25, and CD40L expression) and impaired B-cell differentiation into plasmablasts. Altered NF-κB signaling was evidenced by phosphoflow experiments. These findings coincide with autoinflammatory skin manifestations, systemic infections with progressive lymphopenia, and potentially fatal diseases occurring later in life.
This study broadens the clinical spectrum of IKBKB gain-of-function variants as a progressive immunodeficiency in adulthood.
活化B细胞的核因子κ轻链增强子（NF-κB）信号通路是免疫反应、细胞存活和增殖的关键调节因子。该信号通路失调与多种人类疾病有关，包括先天性免疫缺陷。
我们描述了来自4个无关家庭的16例患者的临床异质性，这些患者在由IKBKB编码的IKK2激酶结构域中存在错义变异。
通过全外显子测序鉴定患者的基因变异（p.V203I和p.M65T）。进行NF-κB报告基因检测以研究NF-κB活性。进行广泛的免疫表型分析、淋巴细胞增殖检测和信号通路分析，以深入了解对B细胞和T细胞表型及功能的影响。
全外显子测序在IKBKB基因中发现了2个功能获得性变异，其中1个是新变异。虽然淋巴细胞数量在年轻时通常正常，但大多数成年患者的B细胞和T细胞数量大幅减少。尽管B细胞和T细胞的增殖能力仍正常，但在第3天表现出激活缺陷（CD70、CD25和CD40L表达），且B细胞分化为浆母细胞受损。磷酸化流式细胞术实验证明NF-κB信号传导发生改变。这些发现与自身炎症性皮肤表现、伴有进行性淋巴细胞减少的全身感染以及生命后期可能致命的疾病相符。
本研究拓宽了IKBKB功能获得性变异作为成年期进行性免疫缺陷的临床谱。
