Human <i>PIK3R1</i> mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2-Reference-Cited by-同舟云学术

Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2

Published:2023-03-21 Issue:6 Volume:220 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Nguyen Tina¹²^ORCID,Lau Anthony¹²^ORCID,Bier Julia¹²^ORCID,Cooke Kristen C.³^ORCID,Lenthall Helen¹^ORCID,Ruiz-Diaz Stephanie¹^ORCID,Avery Danielle T.¹^ORCID,Brigden Henry¹^ORCID,Zahra David¹^ORCID,Sewell William A¹²^ORCID,Droney Luke⁴^ORCID,Okada Satoshi⁵^ORCID,Asano Takaki⁵^ORCID,Abolhassani Hassan⁶⁷^ORCID,Chavoshzadeh Zahra⁸^ORCID,Abraham Roshini S.⁹^ORCID,Rajapakse Nipunie¹⁰^ORCID,Klee Eric W.¹¹^ORCID,Church Joseph A.¹²¹³,Williams Andrew¹⁴¹⁵¹⁶^ORCID,Wong Melanie¹⁴¹⁵¹⁷^ORCID,Burkhart Christoph¹⁸^ORCID,Uzel Gulbu¹⁹^ORCID,Croucher David R.¹²^ORCID,James David E.³²⁰^ORCID,Ma Cindy S.¹²¹⁴^ORCID,Brink Robert¹²^ORCID,Tangye Stuart G.¹²¹⁴^ORCID,Deenick Elissa K.¹²¹⁴^ORCID

Affiliation:

1. Garvan Institute of Medical Research 1 , Darlinghurst, Australia

2. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney 2 , Kensington, Australia

3. Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney 3 , Sydney, Australia

4. Department of Clinical Immunology, Royal Brisbane and Women’s Hospital 4 , Brisbane, Australia

5. Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University 5 , Hiroshima, Japan

6. Department of Biosciences and Nutrition, Division of Clinical Immunology, Karolinska University Hospital Huddinge, Karolinska Institutet 6 , Stockholm, Sweden

7. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences 7 , Tehran, Iran

8. Pediatric Infections Research Center, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences 8 , Tehran, Iran

9. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital 9 , Columbus, OH, USA

10. Department of Pediatric and Adolescent Medicine, Division of Pediatric Infectious Diseases, Mayo Clinic 10 , Rochester, MN, USA

11. Center for Individualized Medicine, Mayo Clinic 11 , Rochester, MN, USA

12. Division of Clinical Immunology and Allergy, Children’s Hospital of Los Angeles 12 , Los Angeles, CA, USA

13. Keck School of Medicine, University of Southern California 13 , Los Angeles, CA, USA

14. Clinical Immunogenomics Research Consortium Australasia 14 , Sydney, Australia

15. Children’s Hospital at Westmead 15 , Westmead, Australia

16. 20Central Clinical School, University of Sydney, Sydney, Australia

17. Faculty of Medicine, University of Sydney 16 , Sydney, Australia

18. Novartis Institutes for Biomedical Research, Novartis Pharma AG 17 , Basel, Switzerland

19. Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health 18 , Bethesda, MD, USA

20. School of Medical Sciences, University of Sydney 19 , Sydney, Australia

Abstract

Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients’ immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.

Funder

National Health and Medical Research Council

American Association of Immunologists

Australian Research Council

Jeffrey Modell Foundation

Sydney Partnership for Health, Education, Research and Enterprise

University of New South Wales

John Brown Cook Foundation

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy