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

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posted on 2021-03-09, 00:57 authored by DT Avery, A Kane, T Nguyen, A Lau, A Nguyen, H Lenthall, K Payne, Wei ShiWei Shi, H Brigden, E French, J Bier, JR Hermes, D Zahra, WA Sewell, D Butt, M Elliott, K Boztug, I Meyts, S Choo, P Hsu, M Wong, LJ Berglund, P Gray, M O’Sullivan, T Cole, SM Holland, CS Ma, C Burkhart, LM Corcoran, TG Phan, R Brink, G Uzel, EK Deenick, SG Tangye
© 2018 Avery et al. Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ 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 p110δ 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 p110δ inhibitors.


This work was supported by program grants (1016953 and 1113904 to S.G. Tangye and R. Brink; 1054925 to L.M. Corcoran), project grants (1088215 to E.K. Deenick and C.S. MaK; 1127157 to S.G. Tangye, E.K. Deenick, C.S. Ma, and T.G. Phan), Principal Research Fellowships (1042925 to S.G. Tangye; 1105877 to R. Brink), a Fulbright Senior Scholarship (S.G. Tangye), a Postgraduate Research Scholarship (1038881 to A. Kane) from the National Health and Medical Research Council of Australia, the Office of Health and Medical Research of the New South Wales Government, the Jeffrey Modell Foundation, the John Cook Brown Foundation and was made possible through Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme Grant (361646). C.S. Ma is supported by an Early-Mid Career Research Fellowship from the New South Wales Government. W. Shi is supported by a WEHI Centenary Fellowship sponsored by Commonwealth Serum Laboratories. T. Nguyen is supported by a Research Training Program Scholarship awarded by the Australian Government.


Publication Date



Journal of Experimental Medicine






23p. (p. 2073-2095)


Rockefeller University Press



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