Disturbed canonical nuclear factor of κ light chain signaling in B cells of patients with common variable immunodeficiency
Disturbed canonical nuclear factor of κ light chain signaling in B cells of patients with common variable immunodeficiency
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DOI：
10.1016/j.jaci.2016.04.043
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发表时间：
2017-01-01
影响因子：
14.2
通讯作者：
Warnatz, Klaus
中科院分区：
文献类型：
--
作者：
Keller, Baerbel;Cseresnyes, Zoltan;Warnatz, Klaus
背景资料：大多数常见变异型免疫缺陷（CVID）患者表现为转换记忆B细胞计数严重减少，一些患者显示CD 21（低）B细胞计数增加（CVID 21低），而另一些患者则没有（CVID 21正常）。B细胞受体（BCR）信号通路的改变可能与CVID患者记忆形成缺陷有关。目的：探讨经典核因子κ轻链（NF κ B）的表达CVID患者的B细胞中的NF-κ B（NF-kappa B）信号传导作为B细胞分化的中心途径。κ B α抑制剂降解（I κ B α）和p65磷酸化，p65的核转位，结果：BCR介导的经典NF-κ B信号在所有成熟的幼稚CVID源性B细胞中均受损。这种损伤在CVID 21低患者的幼稚B细胞中比CVID 21正常患者更严重，并且在CD 21（低）B细胞中最明显。该信号传导缺陷转化为Bcl-xL和I κ B α的诱导减少，这两个基因是经典NF-κ B途径的真正靶基因。CD 40配体和Toll样受体9介导的信号传导改变不太强烈。CD 21（low）B细胞的信号传导，而HIV患者的CD 21（+）B细胞的信号传导没有受到类似的影响。结论：结合先前对Ca（2+）信号传导紊乱的描述，NF-κ B信号传导缺陷的发现，特别是在CVID 21 low患者中，提示广泛的潜在信号传导缺陷，特别影响BCR衍生的信号。鉴于影响Ca（2+）和NF-κ B信号传导的单基因缺陷的免疫表型，后者更有可能导致体液缺陷。CD 21（低）B细胞的BCR信号传导受到强烈干扰是这种细胞类型的特征，与基础疾病无关。
Background: Most patients with common variable immunodeficiency (CVID) present with severely reduced switched memory B-cell counts, and some display an increase of CD21 (low) B-cell counts (CVID 21low), whereas others do not (CVID 21norm). Altered B-cell receptor (BCR) signaling might contribute to the defective memory formation observed in patients with CVID.Objective: We sought to investigate canonical nuclear factor of kappa light chain (NF-kappa B) signaling in B cells from patients with CVID as a central pathway in B-cell differentiation.Methods: Degradation of inhibitor of kappa B alpha (I kappa B alpha) and p65 phosphorylation, nuclear translocation of p65, and regulation of target genes and cell function were investigated after different modes of B-cell stimulation.Results: BCR-mediated canonical NF-kappa B signaling was impaired in all mature naive CVID-derived B cells. This impairment was more profound in naive B cells from CVID 21low patients than CVID 21norm patients and most pronounced in CD21 (low) B cells. The signaling defect translated into reduced induction of Bcl-xL and I kappa B alpha, 2 bona fide target genes of the canonical NF-kappa B pathway. CD40 ligand-and Toll-like receptor 9-mediated signaling were less strongly altered. Signaling in CD21 (low) B cells but not CD21 (+) B cells of patients with HIV was similarly affected.Conclusion: Combined with the previous description of disturbed Ca (2+) signaling, the discovery of NF-kappa B signaling defects, especially in CVID 21low patients, suggests a broad underlying signaling defect affecting especially BCR-derived signals. Given the immune phenotype of monogenic defects affecting Ca (2+) and NF-kappa B signaling, the latter is more likely to contribute to the humoral deficiency. The strongly disturbed BCR signaling of CD21 (low) B cells is characteristic for this cell type and independent of the underlying disease.