Marjolein Wentink1, Virgil Dalm2, Arjan C Lankester3, Pauline A van Schouwenburg1, Liesbeth Schölvinck4, Tomas Kalina5, Radana Zachova6, Anna Sediva6, Annechien Lambeck4, Ingrid Pico-Knijnenburg1, Jacques J M van Dongen7, Malgorzata Pac8, Ewa Bernatowska8, Martin van Hagen2, Gertjan Driessen9, Mirjam van der Burg10. 1. Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 2. 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. 3. Dept. of Pediatric Hematology, Leiden University Medical Centre, Leiden, The Netherlands. 4. University of Groningen, University Medical Centre Groningen, Beatrix Children's Hospital, Department of Paediatrics, Infectious Diseases and Immunology Section, Groningen, The Netherlands. 5. Dept. of Pediatric Hematology and Oncology, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic. 6. Dept. of Immunology, Charles University, 2nd Faculty of Medicine and Motol Hospital, Prague, Czech Republic. 7. 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. 8. Dept. of Immunology, The Children's Memorial Health Institute, Warsaw, Poland. 9. Dept. of Pediatric Immunology and Infectious Diseases, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands. Electronic address: g.driessen@erasmusmc.nl. 10. Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: m.vanderburg@erasmusmc.nl.
Abstract
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.
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 APDSpatients 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 APDSpatients 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: Stuart G Tangye; Julia Bier; Anthony Lau; Tina Nguyen; Gulbu Uzel; Elissa K Deenick Journal: J Clin Immunol Date: 2019-03-25 Impact factor: 8.317
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