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Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections

M. Wentink, V. Dalm, AC. Lankester, PA. van Schouwenburg, L. Schölvinck, T. Kalina, R. Zachova, A. Sediva, A. Lambeck, I. Pico-Knijnenburg, JJ. van Dongen, M. Pac, E. Bernatowska, M. van Hagen, G. Driessen, M. van der Burg,

. 2017 ; 176 (-) : 77-86. [pub] 20170117

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc17023347

Grantová podpora
NV15-28541A MZ0 CEP - Centrální evidence projektů

BACKGROUND: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Citace poskytuje Crossref.org

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$a BACKGROUND: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. METHODS: We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis. RESULTS: We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis. CONCLUSIONS: The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype.
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$a Dalm, Virgil $u Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Dept. of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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$a Lankester, Arjan C $u Dept. of Pediatric Hematology, Leiden University Medical Centre, Leiden, The Netherlands.
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$a van Schouwenburg, Pauline A $u Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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$a Schölvinck, Liesbeth $u University of Groningen, University Medical Centre Groningen, Beatrix Children's Hospital, Department of Paediatrics, Infectious Diseases and Immunology Section, Groningen, The Netherlands.
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$a Kalina, Tomas $u Dept. of Pediatric Hematology and Oncology, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic.
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$a Zachova, Radana $u Dept. of Immunology, Charles University, 2nd Faculty of Medicine and Motol Hospital, Prague, Czech Republic.
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$a Sediva, Anna $u Dept. of Immunology, Charles University, 2nd Faculty of Medicine and Motol Hospital, Prague, Czech Republic.
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$a Lambeck, Annechien $u University of Groningen, University Medical Centre Groningen, Beatrix Children's Hospital, Department of Paediatrics, Infectious Diseases and Immunology Section, Groningen, The Netherlands.
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$a Pico-Knijnenburg, Ingrid $u Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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$a van Dongen, Jacques J M $u Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Dept. of Immunohematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands.
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$a Pac, Malgorzata $u Dept. of Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
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$a Bernatowska, Ewa $u Dept. of Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
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$a van Hagen, Martin $u Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Dept. of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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$a Driessen, Gertjan $u Dept. of Pediatric Immunology and Infectious Diseases, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands. Electronic address: g.driessen@erasmusmc.nl.
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$a van der Burg, Mirjam $u Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: m.vanderburg@erasmusmc.nl.
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