title: Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections.
abstract: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway.
  
  
  
  We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis.
  
  
  
  We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis.
  
  
  
  The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype.
authors.affiliation: Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Wentink
authors.affiliation: Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Dept. of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Virgil
authors.initials: V
authors.lastname: Dalm
authors.affiliation: Dept. of Pediatric Hematology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.affiliation: Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Pauline A
authors.initials: PA
authors.lastname: van Schouwenburg
authors.affiliation: University of Groningen, University Medical Centre Groningen, Beatrix Children's Hospital, Department of Paediatrics, Infectious Diseases and Immunology Section, Groningen, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Schölvinck
authors.affiliation: Dept. of Pediatric Hematology and Oncology, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kalina
authors.affiliation: Dept. of Immunology, Charles University, 2nd Faculty of Medicine and Motol Hospital, Prague, Czech Republic.
authors.forename: Radana
authors.initials: R
authors.lastname: Zachova
authors.affiliation: Dept. of Immunology, Charles University, 2nd Faculty of Medicine and Motol Hospital, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Sediva
authors.affiliation: University of Groningen, University Medical Centre Groningen, Beatrix Children's Hospital, Department of Paediatrics, Infectious Diseases and Immunology Section, Groningen, The Netherlands.
authors.forename: Annechien
authors.initials: A
authors.lastname: Lambeck
authors.affiliation: Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pico-Knijnenburg
authors.affiliation: Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Dept. of Immunohematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.affiliation: Dept. of Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Pac
authors.affiliation: Dept. of Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bernatowska
authors.affiliation: Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Dept. of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: van Hagen
authors.affiliation: Dept. of Pediatric Immunology and Infectious Diseases, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands. Electronic address: g.driessen@erasmusmc.nl.
authors.forename: Gertjan
authors.initials: G
authors.lastname: Driessen
authors.affiliation: Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: m.vanderburg@erasmusmc.nl.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D058543:Class Ia Phosphatidylinositol 3-Kinase; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007239:Infections / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D009154:Mutation / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D010950:Plasma Cells / Q000276:immunology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C588001:PIK3R1 protein, human; C486018:PIK3CD protein, human
keywords: APDS; Apoptosis; B cells; B-cell differentiation; PI3Kδ