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Nat Rev Immunol. 2016 Nov;16(11):702-714. doi: 10.1038/nri.2016.93. Epub 2016 Sep 12.

PI3Kδ and primary immunodeficiencies.

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Molecular Development of the Immune System Section, Laboratory of Immunology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Immunobiology Department, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, UK.
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
Department of Infection, Immunity &Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, UK.


Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

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Conflict of interest statement

C.L.L. collaborates with Novartis. A.C., S.N., A.M.C. and K.O. collaborate with and receive research funding from GSK. K.O. has received consultancy or speaker fees from Karus Pharmaceutical, Merck, Gilead and Incyte.

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