Min Qing, Li Yaxuan, Wu Xuzhe, Yu Meiping, Ying Wenjing, Zhou Qinhua, Hou Jia, Sun Bijun, Hui Xiaoying, Dong Lulu, Meng Xin, Zhang Hai, Hu Ziying, Feng Xiaoqian, Sun Jinqiao, Wang Wenjie, Wang Xiaochuan, Wang Ji-Yang
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China.
Clin Exp Immunol. 2025 Jan 21;219(1). doi: 10.1093/cei/uxae090.
Mutations in the human nuclear factor-κB2 gene (NFKB2) are associated with common variable immunodeficiency (CVID) or combined immunodeficiency diseases (CID), characterized by B-cell lymphopenia, hypogammaglobulinemia, and T-cell dysfunction. This study investigated whether B cells with NFKB2 mutations exhibit intrinsic impairments in activation, class-switch recombination, and differentiation. We analyzed five patients from four unrelated families with CVID, each carrying a heterozygous NFKB2 mutation: P1 (C.2595_2614del, p.A867Gfs12), P2 (C.2597G > A, p.S866N), P3 (C.2540dupT, p.R848Efs38), and P4 and P5 (C.2570_2571insCAGCACA, p.A860Qfs*28). The patients with frameshift mutations (P1, P3, P4, and P5) exhibited truncated proteins detectable in their peripheral blood mononuclear cells, while P2 had a missense mutation. All identified mutations disrupted the processing of p100 into the active p52 form, resulting in NF-κB2 loss of function and IκBδ gain of function. Clinically, P1, P2, and P3 exhibited B-cell lymphopenia, and all five patients presented with hypogammaglobulinemia. Notably, P2 exhibited a markedly low B-cell count, associated with increased proportions of memory B and IgD-CD27- double-negative B cells. In vitro experiments with naïve B cells from P1 and P4 demonstrated decreased survival, impaired activation, and reduced differentiation into CD27+IgD- cells and plasmablasts, while class-switch recombination was unaffected. These findings reveal novel B-cell intrinsic functional defects in patients with NFKB2 mutations.
人类核因子κB2基因（NFKB2）突变与常见变异型免疫缺陷病（CVID）或联合免疫缺陷病（CID）相关，其特征为B细胞淋巴细胞减少、低丙种球蛋白血症和T细胞功能障碍。本研究调查了携带NFKB2突变的B细胞在激活、类别转换重组和分化方面是否存在内在缺陷。我们分析了来自四个无关家庭的五名患有CVID的患者，每人携带一个杂合的NFKB2突变：P1（C.2595_2614del，p.A867Gfs12）、P2（C.2597G>A，p.S866N）、P3（C.2540dupT，p.R848Efs38）以及P4和P5（C.2570_2571insCAGCACA，p.A860Qfs*28）。发生移码突变的患者（P1、P3、P4和P5）在外周血单个核细胞中可检测到截短蛋白，而P2发生了错义突变。所有已鉴定的突变均破坏了p100加工成活性p52形式的过程，导致NF-κB2功能丧失和IκBδ功能获得。临床上，P1、P2和P3表现为B细胞淋巴细胞减少，所有五名患者均有低丙种球蛋白血症。值得注意的是，P2的B细胞计数明显偏低，与记忆B细胞和IgD-CD27双阴性B细胞比例增加有关。对来自P1和P4的初始B细胞进行的体外实验表明，其存活率降低、激活受损，向CD27+IgD-细胞和浆母细胞的分化减少，而类别转换重组未受影响。这些发现揭示了NFKB2突变患者中新型的B细胞内在功能缺陷。
