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Journal of Clinical Immunology

, Volume 39, Issue 2, pp 148–158 | Cite as

Immune Dysregulation and Disease Pathogenesis due to Activating Mutations in PIK3CD—the Goldilocks’ Effect

  • Stuart G. TangyeEmail author
  • Julia Bier
  • Anthony Lau
  • Tina Nguyen
  • Gulbu Uzel
  • Elissa K. Deenick
CME Review

Abstract

“This porridge is too hot!” she exclaimed. So, she tasted the porridge from the second bowl. “This porridge is too cold,” she said. So, she tasted the last bowl of porridge. “Ahhh, this porridge is just right,” she said happily and she ate it all up. While this describes the adventures of Goldilocks in the classic fairytale “The Story of Goldilocks and the Three Bears,” it is an ideal analogy for the need for balanced signaling mediated by phosphatidylinositol-3-kinase (PI3K), a key signaling hub in immune cells. Either too little or too much PI3K activity is deleterious, even pathogenic—it needs to be “just right”! This has been elegantly demonstrated by the identification of inborn errors of immunity in key components of the PI3K pathway, and the impact of these mutations on immune regulation. Detailed analyses of patients with germline activating mutations in PIK3CD, as well as the parallel generation of novel murine models of this disease, have shed substantial light on the role of PI3K in lymphocyte development and differentiation, and mechanisms of disease pathogenesis resulting not only from PIK3CD mutations but genetic lesions in other components of the PI3K pathway. Furthermore, by being able to pharmacologically target PI3K, these monogenic conditions have provided opportunities for the implementation of precision medicine as a therapy, as well as to gain further insight into the consequences of modulating the PI3K pathway in clinical settings.

Keywords

PI3 kinase activated PI3Kinase delta syndrome combined immunodeficiency 

Notes

Funding Information

Research performed in the Tangye and Deenick labs is supported by the National Health and Medical Research Council of Australia, Cancer Council NSW and NIAID, NIH. SGT was a Principal Research Fellow of the NHMRC; JB is supported by the Postgraduate Research Scholarship awarded by Fundação Estudar (Brazil); AL is supported by a Tuition Fee Scholarship from UNSW Sydney; TN is supported by a Research Training Program Scholarship awarded by the Australian Government; GU is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; EKD is a Scientia Research Fellow of UNSW Sydney.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing financial interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Stuart G. Tangye
    • 1
    • 2
    Email author
  • Julia Bier
    • 1
    • 2
  • Anthony Lau
    • 1
    • 2
  • Tina Nguyen
    • 1
    • 2
  • Gulbu Uzel
    • 3
  • Elissa K. Deenick
    • 1
    • 2
  1. 1.Immunology, Garvan Institute of Medical ResearchDarlinghurstAustralia
  2. 2.St Vincent’s Clinical SchoolUniversity of New South WalesDarlinghurstAustralia
  3. 3.Laboratory of Clinical Immunology and MicrobiologyNational Institutes of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA

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