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Mutations

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

Danielle T Avery¹, Alisa Kane^1,2,3,4,5, Tina Nguyen^1,2

¹Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.

The Journal of Experimental Medicine

|July 19, 2018

Summary

This summary is machine-generated.

Gain-of-function mutations in PIK3CD cause immunodeficiency by impairing B cell development and antibody production. Inhibiting PI3K-delta with leniolisib restored immune function in patients and a mouse model.

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Area of Science:

Immunology
Molecular Biology
Genetics

Background:

Gain-of-function (GOF) mutations in PIK3CD lead to primary immunodeficiency.
These mutations impair humoral immune responses after infection or vaccination.
PIK3CD encodes the p110δ subunit of phosphatidylinositide 3-kinase (PI3K).

Purpose of the Study:

To investigate the mechanisms behind immune defects caused by PIK3CD GOF mutations.
To establish a mouse model for studying PIK3CD-related immunodeficiency.
To evaluate the therapeutic potential of p110δ inhibition.

Main Methods:

Studied a cohort of patients with PIK3CD GOF mutations.
Developed a CRISPR/Cas9-mediated mouse model with a pathogenic PIK3CD mutation.
Assessed B cell development, differentiation, and class-switch recombination (CSR) in patients and mice.
Tested the efficacy of leniolisib, a p110δ inhibitor.

Main Results:

Hyperactive PI3K signaling in B cells impaired development and differentiation.
PI3K GOF B cells showed defects in CSR due to reduced activation-induced cytidine deaminase (AID) and plasmablast acquisition.
Leniolisib treatment restored CSR, AID expression, and immunoglobulin secretion.

Conclusions:

Balanced PI3K signaling is crucial for B cell development and humoral immunity.
PIK3CD GOF mutations disrupt B cell function and antibody production.
p110δ inhibitors like leniolisib show therapeutic promise for PIK3CD-related immunodeficiency.