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.

Dept of Immunology Charles University 2nd Faculty of Medicine and Motol Hospital Prague Czech Republic

Dept of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

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

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

Dept of Immunology The Children's Memorial Health Institute Warsaw Poland

Dept of Pediatric Hematology and Oncology Charles University 2nd Faculty of Medicine Prague Czech Republic

Dept of Pediatric Hematology Leiden University Medical Centre Leiden The Netherlands

Dept of Pediatric Immunology and Infectious Diseases Sophia Children's Hospital Erasmus MC Rotterdam The Netherlands

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 randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome

Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib