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      An updated review on activated PI3 kinase delta syndrome (APDS)

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          Abstract

          Activated Phosphoinositide 3-kinase δ syndrome (APDS) is a newly recognised primary immunodeficiency disease. It has currently been a hot topic of clinical research and new data are emerging regarding its pathogenesis, clinical manifestations and treatment. Patients with APDS syndrome have significant autoimmune manifestations and lymphoproliferation. It is important to differentiate APDS from the usual polygenic CVID in view of the availability of targeted therapy like mTOR inhibitors such as Rapamycin and selective PI3Kδ inhibitors. We provide a comprehensive review on this interesting disorder focusing light on its etiology, genetic research and emerging therapy.

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          Most cited references44

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          PI3K in lymphocyte development, differentiation and activation.

          Phosphoinositide 3-kinases (PI3Ks) regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration and metabolism. In the immune system, impaired PI3K signalling leads to immunodeficiency, whereas unrestrained PI3K signalling contributes to autoimmunity and leukaemia. New insights into the role of PI3Ks in lymphocyte biology have been derived from gene-targeting studies, which have identified the PI3K subunits that are involved in B-cell and T-cell signalling. In particular, the catalytic subunit p110delta seems to be adapted to transmit antigen-receptor signalling in B and T cells. Additional recent work has provided new insights into the molecular interactions that lead to PI3K activation and the signalling pathways that are regulated by PI3K.
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            PI3Kδ and primary immunodeficiencies.

            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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              Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib

              Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                14 October 2019
                March 2020
                14 October 2019
                : 7
                : 1
                : 67-74
                Affiliations
                [1]Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                Author notes
                []Corresponding author. Paediatric Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatric Centre, Postgraduate Institute of Medical Education & Research, Sector 12, Chandigarh, 160012, India. rawatamit@ 123456yahoo.com
                Article
                S2352-3042(19)30089-3
                10.1016/j.gendis.2019.09.015
                7063426
                32181277
                bdd2a270-190e-4765-a856-61fdf2212856
                © 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 1 April 2019
                : 21 September 2019
                : 30 September 2019
                Categories
                Article

                lymphoproliferation,activated phosphoinositide 3-kinase δ syndrome (apds),gain of function,immunodeficiency,lymphadenopathy,p110δ-activating mutation causing senescent t cells

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