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Disturbed canonical NF-kB signaling in B cells of CVID patients

Keller, Baerbel and Cseresnyes, Zoltan and Stumpf, Ina and Wehr, Claudia and Fliegauf, Manfred and Bulashevska, Alla and Usadel, Susanne and Grimbacher, Bodo and Rizzi, Marta and Eibel, Hermann and Niesner, Raluca and Warnatz, Klaus (2016) Disturbed canonical NF-kB signaling in B cells of CVID patients. Journal of Allergy and Clinical Immunology, none (none). pp. 1-20. ISSN 0091-6749

Abstract

Background: Most patients with common variable immunodeficiency(CVID) present with severely reduced switched memory B cells and some display an increase of CD21low B cells (CVID 21low) while others don't (CVID 21norm). Altered B-cell receptor (BCR) signaling may contribute to the defective memory formation observed in CVID.
Objective: To investigate canonical NF-kB signaling in CVID patients' B cells as a central pathway in B-cell differentiation.
Methods: Degradation of IkBa and p65 phosphorylation, nuclear translocation of p65 and the regulation of target genes and cell function were investigated after different modes of B-cell stimulation.
Results: BCR-mediated canonical NF-kB signaling was impaired in all mature naïve CVID-derived B cells. This impairment was more profound in naïve B cells of CVID 21low than of 21norm patients and most pronounced in CD21low B cells. The signaling defect translated into reduced induction of Bcl-xL and IkBa, two bona-fide target genes of the canonical
NF-kB pathway. CD40L- and TLR9-mediated signaling was less strongly altered. Signaling in CD21low B cells but not CD21pos B cells of HIV patients was similarly affected.
Conclusion: Combined with the previous description of disturbed Ca2+ signaling the discovery of NF-kB 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-kB 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.

Item Type: Article
Date Deposited: 12 Aug 2016 00:45
Last Modified: 12 Aug 2016 00:45
URI: https://oak.novartis.com/id/eprint/28526

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