Journal Article

Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene

Meng, Xin, Ying, Wenjing, Butte, Manish, Lai, Nannan, Sun, Bijun, Ujhazi, Boglarka, Sun, Jinqiao, Wang, Ying, Walter, Jolan E., Liu, Luyao, Schuetz, Catharina, Min, Qing, Hou, Jia, Wang, Wenjie, Zhou, Qinhua, Hui, Xiaoying, Gordon, Sumai, Wang, Xiaochuan, Csomos, Krisztian, Wang, Ji-Yang, Buchbinder, David

2022

Overview

BackgroundActivated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD . The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM.ObjectiveTo explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS.MethodsClinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells.ResultsThe patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient’s DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes.ConclusionsThe present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 1-Phosphatidylinositol 3-kinase / activated PI3Kδ syndrome (APDS) / Antibodies / Antigens / B cell survival and activation / CD27 antigen / CD27-IgD- double-negative B cells / Cell death / Cell differentiation / Cells / Class switching / Cloning / Flow cytometry / Ig gene class switch recombination / Immunodeficiency / Immunoglobulin D / Immunoglobulin G / Immunoglobulin M / Immunology / Lymphocytes B / Mutation / Penicillin / Phenotypes / plasma cell differentiation / Software