Immunodeficiency-Associated Lymphoid Hyperplasia As a Cause of Intussusception in a Case of Activated PI3K-δ Syndrome

Mettman, Daniel; Thiffault, Isabelle; Dinakar, Chitra; Saunders, Carol J.

doi:10.3389/fped.2017.00071

Cited by 13 publications

(8 citation statements)

References 21 publications

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“…Increased tumor formation in APDS may result from higher proliferation, altered metabolism, and/or reduced cell death of B lymphocytes, leading to the accumulation of mutations in oncogene and/or tumor suppressor genes (Figure ). Alternatively, defective tumor surveillance by T cells could contribute to cancer cell growth.…”

Section: Pi3k and Lymphocyte Tumorigenesismentioning

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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Section: Pi3k and Lymphocyte Tumorigenesismentioning

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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“…Another more recent phenocopy of APDS has been called APDS-like (APDS-L) and is caused by loss-of-function PTEN mutations ( 15 , 16 ). Since the description of APDS in 2013, approximately 214 patients have been described with a spectrum of clinical features described below ( 10 , 11 , 13 – 41 ).…”

Section: Genetic and Molecular Basis Of Apdsmentioning

confidence: 99%

Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency

Carpier

Lucas

2018

Front. Immunol.

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Activated PI3Kδ Syndrome (APDS) is an inherited immune disorder caused by heterozygous, gain-of-function mutations in the genes encoding the phosphoinositide 3-kinase delta (PI3Kδ) subunits p110δ or p85δ. This recently described primary immunodeficiency disease (PID) is characterized by recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to herpesviruses, with Epstein–Barr virus (EBV) infection being most notable. A broad range of PIDs having disparate, molecularly defined genetic etiology can cause susceptibility to EBV, lymphoproliferative disease, and lymphoma. Historically, PID patients with loss-of-function mutations causing defective cell-mediated cytotoxicity or antigen receptor signaling were found to be highly susceptible to pathological EBV infection. By contrast, the gain of function in PI3K signaling observed in APDS patients paradoxically renders these patients susceptible to EBV, though the underlying mechanisms are incompletely understood. At a cellular level, APDS patients exhibit deranged B lymphocyte development and defects in class switch recombination, which generally lead to defective immunoglobulin production. Moreover, APDS patients also demonstrate an abnormal skewing of T cells toward terminal effectors with short telomeres and senescence markers. Here, we review APDS with a particular focus on how the altered lymphocyte biology in these patients may confer EBV susceptibility.

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“…Gain‐of‐function mutation in PI3K ‐δ leads to increased activity in the p110δ catalytic protein (a product of PIK3CD gene), the subunit of PI3K ‐δ . Germline, autosomal dominant mutations lead to the clinical entity called APDS (also called PASLI [P110δ activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency]), wherein patients may suffer from recurrent respiratory infections and progressive airway damage, autoimmune cytopenias, lymphopenia, increased numbers of circulating transitional B cells, increased serum IgM levels, lymphoid hyperplasia, increased risk for malignancy, and impaired vaccine responses . Splice site mutations in PIK3R1 also appear to cause a phenotype similar to APDS …”

Section: Common Variable Immunodeficiencymentioning

confidence: 99%

“…77,78 Germline, autosomal dominant mutations lead to the clinical entity called APDS (also called PASLI [P110 activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency]), wherein patients may suffer from recurrent respiratory infections and progressive airway damage, autoimmune cytopenias, lymphopenia, increased numbers of circulating transitional B cells, increased serum IgM levels, lymphoid hyperplasia, increased risk for malignancy, and impaired vaccine responses. [77][78][79][80][81][82][83] Splice site mutations in PIK3R1 also appear to cause a phenotype similar to APDS. 82,84 Given that PI3K-serves in B-cell proliferation and survival sig- has demonstrated inhibitition of PI3K-signaling and decreased cell viability in B-cell leukemia lines.…”

Section: Activated Phosphoinositide 3-kinase-(pi3k-) Syndromementioning

confidence: 99%

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Rotz

Ware

Kumar

2018

Pediatric Blood & Cancer

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Children, adolescents, and young adults with chronic refractory autoimmune cytopenias represent a rare but challenging group of patients, who are managed frequently by pediatric hematologists. Novel diagnostic tests and genomic discoveries are refining historical diagnoses of Evans syndrome and common variable immunodeficiency, while also elucidating the cellular and molecular basis for these disorders. Genetic characterization of chronic and refractory autoimmune cytopenias has led to targeted therapies with improved clinical outcomes and fewer off-target toxicities. In this review, we focus on the appropriate diagnostic workup, expanded genetic testing, and novel treatment opportunities that are available for these challenging patients.

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Immunodeficiency-Associated Lymphoid Hyperplasia As a Cause of Intussusception in a Case of Activated PI3K-δ Syndrome

Cited by 13 publications

References 21 publications

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

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

Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

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