Baerbel Keller1, Zoltan Cseresnyes2, Ina Stumpf1, Claudia Wehr1, Manfred Fliegauf1, Alla Bulashevska1, Susanne Usadel3, Bodo Grimbacher4, Marta Rizzi1, Hermann Eibel1, Raluca Niesner2, Klaus Warnatz5. 1. Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany. 2. JIMI imaging network and Biophysical Analytics, German Rheumatism Research Center, Leibniz Institute, Berlin, Germany. 3. Infektiologikum Freiburg, Division of Infectious Diseases, Department of Internal Medicine, University Medical Center Freiburg, Freiburg, Germany. 4. Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany; Institute of Immunity and Transplantation, University College London, London, United Kingdom. 5. Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany. Electronic address: klaus.warnatz@uniklinik-freiburg.de.
Abstract
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.
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.
Authors: Manfred Fliegauf; Renate Krüger; Sophie Steiner; Leif Gunnar Hanitsch; Sarah Büchel; Volker Wahn; Horst von Bernuth; Bodo Grimbacher Journal: Front Immunol Date: 2021-04-27 Impact factor: 7.561
Authors: Claudia Schröder; Georgios Sogkas; Manfred Fliegauf; Thilo Dörk; Di Liu; Leif G Hanitsch; Sophie Steiner; Carmen Scheibenbogen; Roland Jacobs; Bodo Grimbacher; Reinhold E Schmidt; Faranaz Atschekzei Journal: Front Immunol Date: 2019-11-14 Impact factor: 7.561
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