Journal article
Germline-activating mutations in PIK3CD compromise B cell development and function
DT Avery, A Kane, T Nguyen, A Lau, A Nguyen, H Lenthall, K Payne, W 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 Show all
Journal of Experimental Medicine | ROCKEFELLER UNIV PRESS | Published : 2018
DOI: 10.1084/jem.20180010
Abstract
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 ..
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Awarded by National Institute of Allergy and Infectious Diseases
Funding Acknowledgements
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.