Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD

Florea, Alina E. Dulau; Braylan, Raul C.; Schafernak, Kristian T.; Williams, Kelli W.; Daub, Janine; Goyal, Rakesh; Puck, Jennifer M.; Rao, V. Koneti; Pittaluga, Stefania; Holland, Steven M.; Uzel, Gülbû; Calvo, Katherine R.

doi:10.1016/j.jaci.2016.08.028

Cited by 64 publications

(44 citation statements)

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“…PBMCs were isolated from healthy anonymous blood donors obtained from the Australian Red Cross Service and patients with PIK3CD GOF mutations (Table I). 19,23,24 Viral infection history of healthy donors was unknown. Whole blood was collected from Australian-based patients and sent immediately to the Garvan Institute of Medical Research.…”

Section: Clinical Evaluationmentioning

confidence: 99%

“…19,31 The other mutations identified in patients in this study (ie, G124D, N334K, E525K, and E1025G) have been reported previously and confirmed to be GOF mutations. 19,23,24 Patients' ages ranged from 4.5 to 67 years (mean, 20.1 years), with patients originating from a variety of ethnicities (Table I). As control subjects, we analyzed PBMCs from 38 healthy donors whose ages ranged from 10 to 71 years (mean, 38.0 years).…”

Section: Patients With Pik3cd Gof Mutations Present With Features Of mentioning

confidence: 99%

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Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

Edwards

Bier

Cole

et al. 2019

Journal of Allergy and Clinical Immunology

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Section: Clinical Evaluationmentioning

confidence: 99%

Section: Patients With Pik3cd Gof Mutations Present With Features Of mentioning

confidence: 99%

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

Edwards

Bier

Cole

et al. 2019

Journal of Allergy and Clinical Immunology

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“…Patients exhibit a paucity of naïve peripheral blood T cells with a large fraction of T cells displaying activation markers. In contrast, B‐cell development is partially blocked, with increased transitional and few circulating memory B cells . Recurrent respiratory infections are the most common feature of APDS.…”

Section: Activated Pi3k‐delta Syndromementioning

confidence: 99%

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Preite

Gómez-Rodríguez

Cannons

et al. 2019

Immunological Reviews

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Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cd E1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8 + T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1 AAA mutant to rescue IgG1 class switching defects in Pik3cd E1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages. K E Y W O R D S APDS/PASLI, autoimmunity, immunodeficiency, phosphatidylinositol 3 kinase, T and B lymphocytes | 155 PREITE ET al. | AC TIVATED PI3K-DELTA SYNDROMEIn 2013-2014, three studies described immunodeficient patients with heterozygous gain-of-function autosomal-dominant mutations in PIK3CD, the gene encoding the catalytic subunit of PI3K p110δ. [3][4][5] At least 11 mutations have now been identified by whole exome sequencing, with the E1021K mutant being most prevalent. 2,6 Based on similar mutations in PI3Kα found in cancers and overgrowth syndromes, p110δ mutations were predicted to activate p110δ. 4,7 Indeed, increased PI3K activity and downstream readouts including increased PIP 3 levels, pAKT and pS6, have been observed in cells from these patients. 3,4 This novel PID has been named "Activated PI3K-delta syndrome" (APDS) or "p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency" (PASLI), hereafter referred to as APDS. Activated PI3K-delta syndrome is a combined immunodeficiency syndrome characterized by altered T-and B-cell development and responses. APDS is associated with frequent respiratory infections, progressive blood lymphopenia, mucosal lymphoid nodules, defective antibody responses, and lymphoma development. 2 Patients exhibit a paucity of naïve peripheral blood T cells with a large fraction of T cells displaying activation markers. In contrast, B-cell development is partially blocked, with increased transitional and few circulating memory B cells. 4,8,9 Recurrent respiratory infections are the most common feature of APDS. However, Epstein-Barr virus (EBV) and/ or cytomegalovirus (CMV) viremia occurs in a substantial fraction of patients, ...

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“…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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Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD

Abstract: Capsule summary Patients with germline mutations in PIK3CD, immunodeficiency, lymphoproliferation, and autoimmunity show a distinct pattern of abnormal B-cell maturation in the bone marrow.

Cited by 64 publications

References 9 publications

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

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

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