PI3Kδ and primary immunodeficiencies View Full Text


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Article Info

DATE

2016-09-12

AUTHORS

Carrie L. Lucas, Anita Chandra, Sergey Nejentsev, Alison M. Condliffe, Klaus Okkenhaug

ABSTRACT

Key PointsPI3Kδ (phosphoinositide 3-kinase-δ) is a key signal transduction node in cells of the immune system. This kinase complex is acutely activated in B cells and T cells after exposure to antigen and controls many aspects of lymphocyte development and differentiation, in part via the AKT, forkhead box O1 (FOXO1) and mechanistic target of rapamycin (mTOR) pathways.Rare loss-of-function mutations affecting PI3Kδ also cause immunodeficiency and immune-mediated pathologies, including colitis. The PI3Kδ inhibitor idelalisib frequently causes colitis at doses tested in leukaemia and lymphoma trials, possibly due to effects on regulatory T (Treg) cells.Activated PI3Kδ syndrome (APDS; also called PASLI disease) is a newly described primary immunodeficiency caused by hyperactive PI3Kδ signalling and resultant T cell senescence and/or death and impaired antibody responses. APDS is generally characterized by recurrent sinopulmonary infections with structural lung damage, viraemia with herpes family viruses, lymphoproliferative disease and increased risk of B cell malignancies.Patients with APDS1 have a heterozygous mutation in PIK3CD, the gene encoding the p110δ catalytic subunit of PI3Kδ, whereas APDS2 patients have a heterozygous mutation in PIK3R1, the gene encoding the p85α regulatory subunit of PI3Kδ. Both sets of mutations lead to higher intrinsic activity of PI3Kδ.To date, most patients with APDS have been treated with antibody replacement therapies and some have also been treated with the mTOR inhibitor rapamycin. In the future, PI3Kδ inhibitors may be used to treat these patients, possibly as the first example of targeted therapy against a hyperactive mutant kinase in primary immunodeficiency. More... »

PAGES

702-714

References to SciGraph publications

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  • 2013-10-28. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency in NATURE IMMUNOLOGY
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  • 2011-02-27. The mammalian Target of Rapamycin (mTOR) regulates T helper cell differentiation through the selective activation of mTORC1 and mTORC2 signaling in NATURE IMMUNOLOGY
  • 2014-06-11. Inactivation of the PI3K p110δ breaks regulatory T cell-mediated immune tolerance to cancer in NATURE
  • 2005-12-28. Restoring function in exhausted CD8 T cells during chronic viral infection in NATURE
  • 2016-04-13. Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature in JOURNAL OF CLINICAL IMMUNOLOGY
  • 2012-10-19. Transcriptional control of effector and memory CD8+ T cell differentiation in NATURE REVIEWS IMMUNOLOGY
  • 2012-09-30. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock in NATURE IMMUNOLOGY
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    http://scigraph.springernature.com/pub.10.1038/nri.2016.93

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    40 schema:description Key PointsPI3Kδ (phosphoinositide 3-kinase-δ) is a key signal transduction node in cells of the immune system. This kinase complex is acutely activated in B cells and T cells after exposure to antigen and controls many aspects of lymphocyte development and differentiation, in part via the AKT, forkhead box O1 (FOXO1) and mechanistic target of rapamycin (mTOR) pathways.Rare loss-of-function mutations affecting PI3Kδ also cause immunodeficiency and immune-mediated pathologies, including colitis. The PI3Kδ inhibitor idelalisib frequently causes colitis at doses tested in leukaemia and lymphoma trials, possibly due to effects on regulatory T (Treg) cells.Activated PI3Kδ syndrome (APDS; also called PASLI disease) is a newly described primary immunodeficiency caused by hyperactive PI3Kδ signalling and resultant T cell senescence and/or death and impaired antibody responses. APDS is generally characterized by recurrent sinopulmonary infections with structural lung damage, viraemia with herpes family viruses, lymphoproliferative disease and increased risk of B cell malignancies.Patients with APDS1 have a heterozygous mutation in PIK3CD, the gene encoding the p110δ catalytic subunit of PI3Kδ, whereas APDS2 patients have a heterozygous mutation in PIK3R1, the gene encoding the p85α regulatory subunit of PI3Kδ. Both sets of mutations lead to higher intrinsic activity of PI3Kδ.To date, most patients with APDS have been treated with antibody replacement therapies and some have also been treated with the mTOR inhibitor rapamycin. In the future, PI3Kδ inhibitors may be used to treat these patients, possibly as the first example of targeted therapy against a hyperactive mutant kinase in primary immunodeficiency.
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