Does enhanced PI3K signalling render APDS patients susceptible to infections by interfering with B cell development and activation?. (360G-Wellcome-103413_Z_13_Z)

Aberrant B cell activity can initiate or aggravate both immunodeficiencies and autoimmunity, and lead to lymphoproliferative disorders. PI3delta (phosphoinositide 3-kinase) is key in the signaling pathways regulating many immune cells, including B and T cells. We have identified patients with a dominant mutation in PI3delta (phosphoinositide 3-kinase ) catalytic subunit, a novel primary antibody immunodeficiency accompanied in some cases by lymphoproliferation. The basis for the phenotype is unknown. We speculate that overactive PI3Kdelta impairs B cell functions downstream of AID (activation induced cytidine deaminase), with failure in the production of protective high affinity class-switched antibodies and promoting cell division. We will investigate patients and mouse models harboring the activating mutation in PI3Kdelta , with emphasis on the effect on B cell functions (cell autonomous and as a result of T regulation) monitoring PI3K activity and expression and function of down stream targets, eg AKT, FOXO1, BLIMP1 and AID. We will test selective PI3Kdelta inhibitors to modulate PI3Kdelta activity and its functional consequences in the context of the activating mutation. We expect that the B cell dysfunction will be reversed by administration of the PI3Kdelta inhibitor in mouse models, and eventually in patients.