Format

Send to

Choose Destination
Clin Immunol. 2017 Mar;176:77-86. doi: 10.1016/j.clim.2017.01.004. Epub 2017 Jan 17.

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

Author information

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.

KEYWORDS:

APDS; Apoptosis; B cells; B-cell differentiation; PI3Kδ

PMID:
28104464
DOI:
10.1016/j.clim.2017.01.004
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center