Fig. 5

Illustration of the PI3Kδ pathway. PI3Kδ is activated through a variety of receptors (shown here is activation via IL-2 and its associated receptor). PI3Kδ typically consists of a catalytic subunit (p110δ) and a regulatory subunit (p85α) and leads to the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by phosphorylating its precursor phosphatidylinositol 4,5-bisphosphate (PIP2), both located in the cell membrane. Downstream PIP3 signaling is mediated by intracellular enzymes, such as the serine/threonine kinase AKT, which phosphorylates the FOXO transcription factors inactivating them, as well as regulators of the mTOR complex 1 (mTORC1), which is in turn activated. Increased activity of the PI3Kδ pathway leads to APDS. Patients with APDS are responsive to mTOR inhibition. More targeted approaches include selective PI3Kδ inhibitors, such as leniolisib or idealisib