Keller, Baerbel, Cseresnyes, Zoltan, Stumpf, Ina, Wehr, Claudia, Fliegauf, Manfred, Bulashevska, Alla, Usadel, Susanne, Grimbacher, Bodo, Rizzi, Marta, Eibel, Hermann, 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