Key Points
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PI3Kδ (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.
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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.
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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.
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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.
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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.
Abstract
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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Change history
30 September 2016
In Table 1 of the original version published online, the 'C416R' mutation was incorrectly referred to as 'C416K'. The authors and Nature Reviews Immunology apologise for this error. It has been corrected in the print and online versions of the article.
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Acknowledgements
The authors thank R. Kissinger at Visual Medical Arts, Research and Technologies Branch, National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH) for artistic contributions to initial drafts of figures 1–4. C.L.L. was supported by the Intramural Research Program of NIAID, NIH and is now supported by a K99/R00 award from the National Heart, Lung and Blood Institute (NHLBI), NIH and Yale University. A.C. and S.N. are supported by fellowships from the Wellcome Trust, UK. S.N., A.M.C. and K.O. are recipients of a programme grant MR/M012328/2 from the UK medical Research Council and GlaxoSmithKline to investigate APDS. S.N. is also supported by the EU FP7 collaborative grant 261441 and the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. A.M.C. also received funding from the British Lung Foundation (RG14-1). Work in the K.O. laboratory is also supported by grants from the Biotechnology and Biological Sciences Research Council (BBSRC: BBS/E/B/000C0407, BBS/E/B/000C0409) and from the Wellcome Trust (095691/Z/11/Z). We are grateful to the many colleagues who have contributed to our understanding of APDS. The authors apologize to those whose contributions could not be cited owing to space constraints.
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C.L.L. collaborates with Novartis. A.C., S.N., A.M.C. and K.O. collaborate with and receive research funding from GlaxoSmithKline. K.O. has received consultancy or speaker fees from Karus Therapeutics, Merck, Gilead and Incyte.
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Glossary
- Activated phosphoinositide 3-kinase-δ (PI3Kδ) syndrome
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(APDS).The term APDS encompasses two syndromes: APDS1 (also known as PASLI-CD), which results from a mutation in the PIK3CD gene that leads to the hyperactivation of the p110δ subunit of PI3Kδ; and APDS2 (also known as PASLI-R1), which results from a splice mutation in PIK3R1 that leads to exon skipping and produces a truncated p85α protein with reduced inhibition of p110δ.
- Primary immunodeficiency
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(PID). An inherited disorder of the immune system that leads to recurrent infections and/or immune dysregulation. Currently there are around 84,000 patients diagnosed worldwide with PID.
- Hypogammaglobulinaemia
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An immune disorder characterized by low serum IgG levels.
- Immune complexes
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Complexes of antigen bound to antibody and, sometimes, components of the complement system. The levels of immune complexes are increased in many autoimmune disorders, in which they become deposited in tissues and cause tissue damage.
- Class-switch recombination
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(CSR).The process by which B cells rearrange their DNA to switch from expressing IgM (or another class of immunoglobulin) to expressing a different immunoglobulin heavy-chain constant region, thereby producing antibody with different effector functions.
- T cell-independent (TI) antibody response
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An antibody response to polymeric antigens, such as polysaccharides and lipids, that does not require T cell help.
- Activation-induced cytidine deaminase
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(AID). An enzyme that is required for two crucial events in the germinal centre: somatic hypermutation and class-switch recombination.
- Somatic hypermutation
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(SHM). A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells thatproduce high-affinity antibody, SHM leads to affinity maturation of B cells in germinal centres.
- Germinal centre reaction
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Germinal centres are specialized structures within spleens and lymph nodes where B cells present antigen to T cells and, in return, are selected to undergo class-switch recombination and somatic hypermutation.
- Follicular helper T cells
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(TFH cells). CD4+ T helper cells that are essential for the induction of class switching in the germinal centres of secondary follicles during antibody responses to T cell-dependent antigens.
- Transitional B cells
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Immature B cells that have left the bone marrow for the spleen and are precursors of follicular B cells, marginal zone B cells and B1 B cells.
- Senescence
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A state in which a cell fails to progress through the cell cycle owing to activation of the DNA damage response, which can occur upon extreme shortening of telomeres.
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Lucas, C., Chandra, A., Nejentsev, S. et al. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol 16, 702–714 (2016). https://doi.org/10.1038/nri.2016.93
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DOI: https://doi.org/10.1038/nri.2016.93
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