Disturbed canonical nuclear factor of κ light chain signaling in B cells of patients with common variable immunodeficiency

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• 作者：Baerbel Keller ; PhD^a ; Zoltan Cseresnyes ; PhD^b ; Ina Stumpf^a ; Claudia Wehr ; MD^a ; Manfred Fliegauf ; PhD^a ; Alla Bulashevska ; PhD^a ; Susanne Usadel ; MD^c ; Bodo Grimbacher ; MD^a ; ^d ; Marta Rizzi ; MD^a ; Hermann Eibel ; PhD^a ; Raluca Niesner ; PhD^b ; Klaus Warnatz ; MD^a ; ^{klaus.warnatz@uniklinik-freiburg.de}
• 关键词：Common variable immunodeficiency ; B cells ; CD21low B cells ; canonical nuclear factor of κ light chain ; signaling ; B-cell receptor ; Toll-like receptor 9 ; CD40 ; HIV
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：139
• 期：1
• 页码：220-231.e8
• 全文大小：4566 K
• 卷排序：139

文摘

Most patients with common variable immunodeficiency (CVID) present with severely reduced switched memory B-cell counts, and some display an increase of CD21low 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.ObjectiveWe sought to investigate canonical nuclear factor of κ light chain (NF-κB) signaling in B cells from patients with CVID as a central pathway in B-cell differentiation.MethodsDegradation of inhibitor of κBα (IκBα) and p65 phosphorylation, nuclear translocation of p65, and regulation of target genes and cell function were investigated after different modes of B-cell stimulation.ResultsBCR-mediated canonical NF-κB 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 CD21low B cells. The signaling defect translated into reduced induction of Bcl-xL and IκBα, 2 bona fide target genes of the canonical NF-κB pathway. CD40 ligand– and Toll-like receptor 9–mediated signaling were less strongly altered. Signaling in CD21low B cells but not CD21+ B cells of patients with HIV was similarly affected.ConclusionCombined with the previous description of disturbed Ca2+ signaling, the discovery of NF-κB 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 Ca2+ and NF-κB signaling, the latter is more likely to contribute to the humoral deficiency. The strongly disturbed BCR signaling of CD21low B cells is characteristic for this cell type and independent of the underlying disease.