Germline-activating mutations in PIK3CD compromise B cell development and function.
Avery DT., Kane A., Nguyen T., Lau A., Nguyen A., Lenthall H., Payne K., Shi W., Brigden H., French E., Bier J., Hermes JR., Zahra D., Sewell WA., Butt D., Elliott M., Boztug K., Meyts I., Choo S., Hsu P., Wong M., Berglund LJ., Gray P., O'Sullivan M., Cole T., Holland SM., Ma CS., Burkhart C., Corcoran LM., Phan TG., Brink R., Uzel G., Deenick EK., Tangye SG.
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.