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

Publication date: Available online 17 January 2017
Source:Clinical Immunology
Author(s): Marjolein Wentink, Virgil Dalm, Arjan C. Lankester, Pauline A. van Schouwenburg, Liesbeth Schölvinck, Tomas Kalina, Radana Zachova, Anna Sediva, Annechien Lambeck, Ingrid Pico-Knijnenburg, Jacques J.M. van Dongen, Malgorzata Pac, Ewa Bernatowska, Martin van Hagen, Gertjan Driessen, Mirjam van der Burg
BackgroundMutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway.MethodsWe 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.ResultsWe 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.ConclusionsThe 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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