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

Background 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...

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Published in:Journal of allergy and clinical immunology 2017-01, Vol.139 (1), p.220-231.e8
Main Authors: Keller, Baerbel, PhD, Cseresnyes, Zoltan, PhD, Stumpf, Ina, Wehr, Claudia, MD, Fliegauf, Manfred, PhD, Bulashevska, Alla, PhD, Usadel, Susanne, MD, Grimbacher, Bodo, MD, Rizzi, Marta, MD, Eibel, Hermann, PhD, Niesner, Raluca, PhD, Warnatz, Klaus, MD
Format: Article
Language:English
Subjects:
Adult
Aged
Allergy and Immunology
B-cell receptor
B-Lymphocytes - immunology
B cells
canonical nuclear factor of κ light chain
CD21low B cells
CD40
Cell Differentiation
Common variable immunodeficiency
Common Variable Immunodeficiency - immunology
Female
HIV
Humans
Male
Middle Aged
NF-kappa B - immunology
Receptors, Antigen, B-Cell - immunology
Receptors, Complement 3d - immunology
Signal Transduction
signaling
Toll-like receptor 9
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Summary:Background 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. Objective We 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. Methods Degradation 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. Results BCR-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. Conclusion Combined 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.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2016.04.043