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J Exp Med. 2018 Oct 1;215(10):2485-2496. doi: 10.1084/jem.20180617. Epub 2018 Sep 7.

Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses.

Author information

1
Seattle Children's Research Institute, Seattle, WA.
2
Department of Immunology, University of Washington, Seattle, WA.
3
King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
4
Department of Pediatrics, University of Washington, Seattle, WA.
5
Department of Pharmacology, University of Washington, Seattle, WA.
6
Seattle Children's Research Institute, Seattle, WA drawling@u.washington.edu.

Abstract

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.

PMID:
30194267
PMCID:
PMC6170176
DOI:
10.1084/jem.20180617
[Indexed for MEDLINE]
Free PMC Article

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