Germline-activating mutations in PIK3CD compromise B cell development and function Academic Article uri icon


  • 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.


  • Avery, Danielle T
  • Kane, Alisa
  • Nguyen, Tina
  • Lau, Anthony
  • Nguyen, Akira
  • Lenthall, Helen
  • Payne, Kathryn
  • Shi, Wei
  • Brigden, Henry
  • French, Elise
  • Bier, Julia
  • Hermes, Jana R
  • Zahra, David
  • Sewell, William A
  • Butt, Danyal
  • Elliott, Michael
  • Boztug, Kaan
  • Meyts, Isabelle
  • Choo, Sharon
  • Hsu, Peter
  • Wong, Melanie
  • Berglund, Lucinda J
  • Gray, Paul
  • O’Sullivan, Michael
  • Cole, Theresa
  • Holland, Steven M
  • Ma, Cindy S
  • Burkhart, Christoph
  • Corcoran, Lynn M
  • Phan, Tri Giang
  • Brink, Robert
  • Uzel, Gulbu
  • Deenick, Elissa K
  • Tangye, Stuart G

publication date

  • August 6, 2018

has subject area