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

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.