Immunodeficiency: primary or acquired
Humans with gain of function (GOF) mutations in PIK3CD, encoding the p110d subunit of phosphatidylinositol 3-kinase, have an immunodeficiency characterized by clinical features consistent with a significant defect in the function of their humoral immune response. These include increased susceptibility to sinopulmonary infections and poor antibody responses to common encapsulated respiratory pathogens. In addition they have strikingly increased peripheral blood transitional B cell numbers pointing to a developmental abnormality in B cells.
To explore the consequences of Phosphatidylinositol 3-kinase GOF on both B cell development and function, we analyzed B cells from both mouse and humans with GOF mutations in the gene encoding PI3 kinase δ. Mice were generated using CRISPR/Cas9 gene editing to introduce the most-common disease causing mutation (E1021K) into Pi3kcd.
Analysis of bone marrow from both mice and humans revealed disrupted B cell development. Investigation of antigen-specific T-cell dependent B cell responses using mice expressing a transgenic BCR specific for hen egg lysozyme (HEL) combined with Pi3kcd GOF showed defects in Ig class switching and specific antibody generation that recapitulate the humoral immune defects seen in humans with PIK3CD GOF mutations.
This study provides new insights into the molecular and cellular defects underlying the humoral defects in patients with PI3KCD GOF mutations.