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

Avery, DT; Kane, A; Nguyen, T; Lau, A; Nguyen, A; Lenthall, H; Payne, K; Shi, W; Brigden, H; French, E; Bier, J; Hermes, JR; Zahra, D; SEWELL, WA; Butt, D; ELLIOTT, M; Boztug, K; Meyts, I; Choo, S; Hsu, P; Wong, M; Berglund, LJ; Gray, P; O&#39;Sullivan, M; Cole, T; Holland, SM; Ma, CS; Burkhart, C; Corcoran, LM; Phan, TG; Brink, R; Uzel, G; Deenick, EK; Tangye, SG

Author(s): Avery, DT; Kane, A; Nguyen, T; Lau, A; Nguyen, A; Lenthall, H; Payne, K; Shi, W; Brigden, H; French, E; Bier, J; Hermes, JR; Zahra, D; SEWELL, WA; Butt, D; ELLIOTT, M; Boztug, K; Meyts, I; Choo, S; Hsu, P; Wong, M; Berglund, LJ; Gray, P; O'Sullivan, M; Cole, T; Holland, SM; Ma, CS; Burkhart, C; Corcoran, LM; Phan, TG; Brink, R; Uzel, G; Deenick, EK; Tangye, SG;
Details: Publication Year 2018-08-06,Volume 215,Issue #8,Page 2073-2095
Journal Title: Journal of Experimental Medicine
Publication Type: Journal Article
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.
Publisher: Rockefeller Press
Research Division(s): Molecular Immunology; Bioinformatics
PubMed ID: 30018075
Publisher's Version: https://doi.org/10.1084/jem.20180010
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-10-11 04:23:13

Last Modified: 2018-10-12 12:10:41