Germline-activating mutations in PIK3CD compromise B cell development and function-Reference-Cited by-同舟云学术

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

Published:2018-07-17 Issue:8 Volume:215 Page:2073-2095
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Avery Danielle T.¹^ORCID,Kane Alisa¹²³⁴⁵,Nguyen Tina¹²,Lau Anthony¹²,Nguyen Akira¹²^ORCID,Lenthall Helen¹,Payne Kathryn¹^ORCID,Shi Wei⁶⁷,Brigden Henry¹,French Elise¹,Bier Julia¹²^ORCID,Hermes Jana R.¹,Zahra David¹,Sewell William A.¹²⁸^ORCID,Butt Danyal¹²^ORCID,Elliott Michael⁹¹⁰,Boztug Kaan¹¹¹²¹³^ORCID,Meyts Isabelle¹⁴,Choo Sharon¹⁵,Hsu Peter⁵¹⁶,Wong Melanie⁵¹⁶,Berglund Lucinda J.⁵¹⁷¹⁸^ORCID,Gray Paul⁵¹⁹,O’Sullivan Michael²⁰^ORCID,Cole Theresa¹⁵,Holland Steven M.²¹^ORCID,Ma Cindy S.¹²⁵,Burkhart Christoph²²,Corcoran Lynn M.⁶⁷^ORCID,Phan Tri Giang¹²⁵^ORCID,Brink Robert¹²⁵,Uzel Gulbu²¹,Deenick Elissa K.¹²⁵^ORCID,Tangye Stuart G.¹²⁵^ORCID

Affiliation:

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

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.

Funder

National Health and Medical Research Council

Office of Health and Medical Research

New South Wales Government

Jeffrey Modell Foundation

John Cook Brown Foundation

Victorian State Government

Australian Government

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy