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Germline-activating mutations in PIK3CD compromise B cell development and function

Abstract

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110delta subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110delta inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110delta inhibitors.

Type Journal
ISBN 1540-9538 (Electronic) 0022-1007 (Linking)
Authors Avery, D. T.; Kane, A.; Nguyen, T.; Lau, A.; Nguyen, A.; Lenthall, H.; Payne, K.; Shi, W.; Brigden, H.; French, E.; Bier, J.; Hermes, J. R.; Zahra, D.; Sewell, W. A.; Butt, D.; Elliott, M.; Boztug, K.; Meyts, I.; Choo, S.; Hsu, P.; Wong, M.; Berglund, L. J.; Gray, P.; O'Sullivan, M.; Cole, T.; Holland, S. M.; Ma, C. S.; Burkhart, C.; Corcoran, L. M.; Phan, T. G.; Brink, R.; Uzel, G.; Deenick, E. K.; Tangye, S. G.
Responsible Garvan Author Prof Stuart Tangye
Publisher Name JOURNAL OF EXPERIMENTAL MEDICINE
Published Date 2018-08-06
Published Volume 215
Published Issue 8
Published Pages 2073-2095
Status Published in-print
DOI 10.1084/jem.20180010
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/30018075