title: Disturbed canonical nuclear factor of κ light chain signaling in B cells of patients with common variable immunodeficiency.
abstract: Most patients with common variable immunodeficiency (CVID) present with severely reduced switched memory B-cell counts, and some display an increase of CD21lowB-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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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 CD21lowB 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 CD21lowB cells but not CD21+B cells of patients with HIV was similarly affected.
  
  
  
  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 CD21lowB cells is characteristic for this cell type and independent of the underlying disease.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Keller
authors.affiliation: JIMI imaging network and Biophysical Analytics, German Rheumatism Research Center, Leibniz Institute, Berlin, Germany.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Cseresnyes
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Stumpf
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wehr
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Fliegauf
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
authors.forename: Alla
authors.initials: A
authors.lastname: Bulashevska
authors.affiliation: Infektiologikum Freiburg, Division of Infectious Diseases, Department of Internal Medicine, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Usadel
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany; Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: JIMI imaging network and Biophysical Analytics, German Rheumatism Research Center, Leibniz Institute, Berlin, Germany.
authors.forename: Raluca
authors.initials: R
authors.lastname: Niesner
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany. Electronic address: klaus.warnatz@uniklinik-freiburg.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D017464:Receptors, Complement 3d / Q000276:immunology; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d
keywords: B-cell receptor; B cells; CD21(low) B cells; CD40; Common variable immunodeficiency; HIV; Toll-like receptor 9; canonical nuclear factor of κ light chain; signaling