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J Exp Med. 2018 Aug 6;215(8):2073-2095. doi: 10.1084/jem.20180010. Epub 2018 Jul 17.

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

Avery DT1, Kane A1,2,3,4,5, Nguyen T1,2, Lau A1,2, Nguyen A1,2, Lenthall H1, Payne K1, Shi W6,7, Brigden H1, French E1, Bier J1,2, Hermes JR1, Zahra D1, Sewell WA1,2,8, Butt D1,2, Elliott M9,10, Boztug K11,12,13, Meyts I14, Choo S15, Hsu P5,16, Wong M5,16, Berglund LJ5,17,18, Gray P5,19, O'Sullivan M20, Cole T15, Holland SM21, Ma CS1,2,5, Burkhart C22, Corcoran LM6,7, Phan TG1,2,5, Brink R1,2,5, Uzel G21, Deenick EK23,2,5, Tangye SG24,2,5.

Author information

1
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
2
St. Vincent's Clinical School, University of New South Wales (UNSW), New South Wales, Australia.
3
Department of Immunology and Allergy, Liverpool Hospital, Liverpool, New South Wales, Australia.
4
South Western Sydney Clinical School, UNSW Sydney, Liverpool, New South Wales, Australia.
5
Clinical Immunogenomics Research Consortia Australia (CIRCA), Sydney, New South Wales, Australia.
6
Molecular Immunology and Bioinformatics Divisions, Walter & Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia.
7
University of Melbourne, Parkville, Victoria, Australia.
8
Immunology Department, SydPath, St. Vincent's Hospital, Sydney, New South Wales, Australia.
9
Sydney Medical School, University of Sydney, Sydney, Australia.
10
Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
11
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
12
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
13
St. Anna Children's Hospital and Children's Cancer Research Institute, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
14
Department of Immunology and Microbiology, Childhood Immunology, Department of Pediatrics, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
15
Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Victoria, Australia.
16
Children's Hospital at Westmead, New South Wales, Australia.
17
Immunopathology Department, Westmead Hospital, Westmead, New South Wales, Australia.
18
Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia.
19
University of New South Wales School of Women's and Children's Health, New South Wales, Australia.
20
Department of Immunology and Allergy, Princess Margaret Hospital, Subiaco, Western Australia, Australia.
21
Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
22
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
23
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia e.deenick@garvan.org.au.
24
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia s.tangye@garvan.org.au.

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 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.

PMID:
30018075
PMCID:
PMC6080914
[Available on 2019-02-06]
DOI:
10.1084/jem.20180010

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