| First Author | Avery DT | Year | 2018 |
| Journal | J Exp Med | Volume | 215 |
| Issue | 8 | Pages | 2073-2095 |
| PubMed ID | 30018075 | Mgi Jnum | J:292599 |
| Mgi Id | MGI:6201898 | Doi | 10.1084/jem.20180010 |
| Citation | Avery DT, et al. (2018) Germline-activating mutations in PIK3CD compromise B cell development and function. J Exp Med 215(8):2073-2095 |
| abstractText | Gain-of-function (GOF) mutations in PIK3CD, encoding the p110delta 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 p110delta 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 p110delta inhibitors. |
