Clinical immunology (Orlando, Fla.) · 2017
Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections.
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Wentink Marjolein, Dalm Virgil, Lankester Arjan C, van Schouwenburg Pauline A, Schölvinck Liesbeth, Kalina Tomas, Zachova Radana, Sediva Anna, Lambeck Annechien, Pico-Knijnenburg Ingrid, van Dongen Jacques J M, Pac Malgorzata, Bernatowska Ewa, van Hagen Martin, Driessen Gertjan, van der Burg Mirjam
Аннотация
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.
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.
Предметные рубрики MeSH
AdolescentAdultAgammaglobulinemiaB-LymphocytesCell DifferentiationChildChild, PreschoolClass I Phosphatidylinositol 3-KinasesClass Ia Phosphatidylinositol 3-KinaseFemaleHumansImmunoglobulin Class SwitchingInfectionsLymphocyte ActivationMaleMutationPhosphatidylinositol 3-KinasesPhosphorylationPlasma CellsPrecursor Cells, B-LymphoidProto-Oncogene Proteins c-aktRecurrenceSignal TransductionSomatic Hypermutation, ImmunoglobulinYoung Adult