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Pathogenic germline activating mutations in PIK3CD compromise B-cell development and function, underlying humoral defects in human primary immunodeficiency

Avery, Danielle A and Kane, Elisa and Nguyen, Tina and Lau, Anthony and Nguyen, Akira and Payne, Kathryn and Lenthall, Ellen and Wei, Shi and Brigden, henry and French , Elise and Bier, Julia and Hermes, Jana R and Zahra, David and Sewell, William and Boztug, Kaan and Meyts, Isabelle and Choo, Sharon and Hsu, Peter and Wong, Melanie and Berglund, Lucinda and Gray, Paul and O'Sullivan, Michael and Cole, Therese and Holland, Steven M and Ma, Cindy S and Burkhart, Christoph and Corcoran, Lynn M and Phan, Tri G and Brink, Robert and Uzel, Gulbu and Deenick, Elissa K and Tanguye, Stuart G (2018) Pathogenic germline activating mutations in PIK3CD compromise B-cell development and function, underlying humoral defects in human primary immunodeficiency. Journal of Experimental Medicine.

Abstract

Gain of function (GOF) mutations in PIK3CD, encoding the p110d subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization and reduced levels of Ag-specific serum Ig. To establish mechanisms underlying these humoral immune defects, we studied a large cohort (n=39) of patients with PIK3CD GOF mutations, and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common disease-causing mutation in Pik3cd. In both species, hyperactive PI3K severely affected B-cell development, evidenced by the accumulation of progenitor cells in the bone marrow and immature transitional B cells in the periphery, and a paucity of total and class switched memory B cells. Furthermore, PI3K GOF B cells exhibited intrinsic functional defects in generating class switched humoral immune responses due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a full plasmablast gene signature and phenotype. Importantly, defects in class switching, AID expression and Ig secretion were completely restored by leniolisib, a specific inhibitor of p110d. Overall, 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 inhibitors of p110d.

Item Type: Article
Date Deposited: 01 Aug 2018 00:45
Last Modified: 01 Aug 2018 00:45
URI: https://oak.novartis.com/id/eprint/36496

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