Genetic defects in PI3K delta affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections
Abstrakt
Background: Mutations in PIK3CD and PIK3R1 cause activated PI3K-8 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. (C) 2017 Published by Elsevier Inc