Gain-of-function mutations in <em>Pik3cd</em> result in dysregulation of B cells at multiple stages — ASN Events
  1. Schedule
  2. Poster Session One & Burnet Oration Cocktail Function
  3. Gain-of-function mutations in Pik3cd result in dysregulation of B cells at multiple stages

Gain-of-function mutations in Pik3cd result in dysregulation of B cells at multiple stages (#200)

Elissa K Deenick 1 2 , Alisa Kane 1 2 , Anthony Lau 1 2 , Elise French 1 3 , Henry Brigden 1 3 , Julia Bier 1 2 , Robert Brink 1 2 , Stuart G Tangye 1 2
  1. Garvan Institute, Darlinghurst, NSW, Australia
  2. St Vincents Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
  3. University of Bath, Bath, UK

Gain of function (GOF) mutations in PIK3CD, encoding the p110δ subunit of PI3-kinase, cause a primary immunodeficiency characterized by recurrent respiratory infections, increased susceptibility to herpes virus (EBV, CMV, VZV) infection, poor Ab responses to polysaccharide Ags, altered serum immunoglobulin levels and B-cell lymphoma. Interestingly, many of these patients also suffer from a range of autoimmune conditions. Overall this spectrum of symptoms suggests a dysregulation of the humoral immune response is a primary contributor to the pathology of these patients.

To better understand how over active PI3K contributes to dysregulated B cell responses we generated a mouse model using CRISPR/Cas9 to introduce the common disease-causing mutation (E1021K) into Pik3cd. This mouse model also allowed us to determine whether changes observed in B cell responses were cell intrinsic or were secondary to PI3K over activation in other cell types.

These studies, revealed a clear defect in B cell development in the presence of the GOF mutations that was cell intrinsic. Further, B cells also displayed a cell intrinsic defect in isotype switching both in vitro and in vivo. However, many other aspects of the in vivo B cell response remained intact. These defects provide an explanation, at least in part, for the dysregulated antibody responses observed in these patients that results in both immune deficiency and autoimmunity.

#ASI2017QLD