Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

Elkaim, Élodie; Neven, Bénédicte; Bruneau, Julie; Mitsui-Sekinaka, Kanako; Stanislas, Aurélie; Heurtier, Lucie; Lucas, Carrie L.; Matthews, Helen; Deau, Marie-Céline; Sharapova, Svetlana O.; Curtis, James; Reichenbach, Janine; Glastre, Catherine; Parry, David; Arumugakani, Gururaj; McDermott, Elizabeth; Kılıç, Sara Şebnem; Yamashita, Motoi; Moshous, Despina; Lamrini, Hicham; Otremba, Burkhard; Gennery, Andrew R.; Coulter, Tanya; Quinti, Isabella; Stéphan, Jean Louis; Lougaris, Vassilios; Brodszki, Nicholas; Barlogis, Vincent; Asano, Takaki; Galicier, Lionel; Boutboul, David; Nonoyama, Shigeaki; Cant, Andrew J.; Imai, Kohsuke; Pïcard, Capucine; Nejentsev, Sergey; Molina, Thierry Jo; Lenardo, Michael J.; Savic, Sinisa; Cavazzana, Marina; Fischer, Alain; Durandy, Anne; Kracker, Sven

doi:10.1016/j.jaci.2016.03.022

Cited by 217 publications

(315 citation statements)

References 19 publications

(27 reference statements)

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“…However, the severity of respiratory infections and resulting structural damage in the lungs do not correlate well with the reduction in B cell numbers or the extent of immunoglobulin deficiency6, 7, and immunoglobulin replacement therapy alone does not appear to limit the progress of lung damage in patients with APDS 6, 7. One explanation for this apparent discrepancy is that PI3Kδ hyperactivation causes additional defects (such as altered T cell functions or innate immune cell dysfunction) that also contribute to an increased susceptibility to respiratory bacterial infections.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

“…Subsequently, a number of additional studies have identified APDS patients with mutations in PIK3CD 5, 7, 64–69 or PIK3R1 6, 70–73. Patients with GOF mutations in either of these genes appear to largely phenocopy each other, despite the fact that p85α is ubiquitously expressed and can pair with p110α and p110β in addition to p110δ.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

“…Increased susceptibility to viral infection and poor recall responses of memory T cells differentiate APDS from isolated hypogammaglobulinemia 1–4, hence APDS should be considered a combined immunodeficiency5. More than 100 patients have been reported to date with APDS, but the precise incidence is not yet known6, 7.…”

Section: Introductionmentioning

confidence: 99%

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PI3Kδ and primary immunodeficiencies

et al. 2016

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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) or 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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Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

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PI3Kδ and primary immunodeficiencies

et al. 2016

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“…3,11,10 Since the diagnosis of APDS1, P1 and P3 were treated with rapamycin and are under consideration for HSCT. Inhibitors specific for p110δ are currently in clinical trials (EudraCT Numbers: 2015-002900-10; 2015-005541-30; 2014-003876-22; 2015-004876-31) and could offer a new treatment option for APDS patients with possibly higher efficiency and less unwanted side effects.…”

Section: 13mentioning

confidence: 99%

“…It highlights that mutations occurring in different parts of the gene can lead to the very same consequences, and should thus be screened in patients with a phenotype resembling APDS. Jean-Marc Plaza, 4 Mélanie Parisot, 5 Benoit Dumont, 6 Delphine Turpin, 7 Etienne Merlin, 8 Despina Moshous, 1,2,9 Nathalie Aladjidi, 10 Bénédicte Neven, 1,2,9 Capucine Picard, 1,2,3 Marina Cavazzana, 1,2,11 Alain Fischer, 1,2,9,12 Anne Durandy, 1,2 Jean-Louis Stephan 6 and Sven Kracker …”

Section: 13mentioning

confidence: 99%

Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1)

et al. 2017

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Extended immunophenotyping reference values in a healthy pediatric population

García-Prat

Álvarez‐Sierra

Aguiló-Cucurull

et al. 2018

Cytometry Part B Clinical

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Background For the accurate diagnosis of immunodeficiencies is crucial to compare patients’ immunology laboratory values with age‐sex matched controls, yet there is a paucity of normal values for most populations. Objectives To define appropriate reference values of extended lymphocyte subpopulations and T‐cell receptor excision circle (TRECs) levels in healthy pediatric donors between 1 month and 18 years of age. Methods Extended immunophenotyping values were obtained by analysis of multiparameter flow cytometry panels for the following subpopulations: CD4+ and CD8+ Naive, Effector, Effector Memory and Central Memory, T helper subpopulations and their degrees of activation, T Regulatory cells, Recent Thymic Emigrants (RTE), B Lymphocyte subpopulations (Transitional, Naive, Preswitch‐Memory, Switch‐Memory, Plasmablasts, CD21low, and Exhausted), and subpopulations for Monocytes, NK cells and Dendritic Cells. Results Median values and the 10th and 90th percentiles were obtained for 32 lymphocyte and monocyte subpopulations, and for TRECs levels in each age group of children. Naive CD4+ and CD8+ T‐cell populations tended to decrease with age, with significant difference between the groups, in parallel with the reduction in thymic function assessed by TRECs counts and the recent thymic emigrant population. Relative numbers of Th cell populations tended to increase with age. The percentage of class‐switched B cell populations showed a significant increase between the youngest group and the others. Conclusion This study provides essential data for interpreting extended immunophenotyping profiles in the pediatric and young adult populations, which could be of value for the diagnosis of PIDs and immune‐mediated diseases, particularly those associated with subtle immunological abnormalities. © 2018 International Clinical Cytometry Society

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Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

Cited by 217 publications

References 19 publications

PI3Kδ and primary immunodeficiencies

PI3Kδ and primary immunodeficiencies

Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1)

Extended immunophenotyping reference values in a healthy pediatric population

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