idelalisib and Immunologic-Deficiency-Syndromes

Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.

Topics: Animals; Autoimmunity; Cell Differentiation; Class I Phosphatidylinositol 3-Kinases; Humans; Immune System; Immunity, Humoral; Immunologic Deficiency Syndromes; Mice; Mutation; Phenotype; Purines; Quinazolinones; Signal Transduction

Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in either the leukocyte-restricted p110δ catalytic (

Topics: Catalytic Domain; Cell Membrane; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Enzyme Assays; Enzyme Inhibitors; Gain of Function Mutation; Humans; Immunologic Deficiency Syndromes; Mass Spectrometry; Models, Molecular; Phenotype; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Protein Conformation; Purines; Quinazolinones; Randomized Controlled Trials as Topic; Sequence Deletion