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 A^1,^2,^3,^4,⁵, Nguyen T^1,², Lau A^1,², Nguyen A^1,², Lenthall H¹, Payne K¹, Shi W^6,⁷, Brigden H¹, French E¹, Bier J^1,², Hermes JR¹, Zahra D¹, Sewell WA^1,^2,⁸, Butt D^1,², Elliott M^9,¹⁰, Boztug K^11,^12,¹³, Meyts I¹⁴, Choo S¹⁵, Hsu P^5,¹⁶, Wong M^5,¹⁶, Berglund LJ^5,^17,¹⁸, Gray P^5,¹⁹, O'Sullivan M²⁰, Cole T¹⁵, Holland SM²¹, Ma CS^1,^2,⁵, Burkhart C²², Corcoran LM^6,⁷, Phan TG^1,^2,⁵, Brink R^1,^2,⁵, Uzel G²¹, Deenick EK^23,^2,⁵, Tangye SG^24,^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.