Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene
Wenjie Wang, Qing Min, Nannan Lai, Krisztián Csomós, Ying Wang, Luyao Liu, Xin Meng, Jinqiao Sun, Jia Hou, Wenjing Ying, Qinhua Zhou, Bijun Sun, Xiaoying Hui, Boglárka Ujházi, Sumai Gordon, David Buchbinder, Catharina Schuetz, Manish J. Butte, Jolán E. Walter, Xiaochuan Wang, Jiyang Wang
Abstract
Background Activated 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. Objective To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS. Methods Clinical 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. Results The 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. Conclusions The 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.