Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling

Walsh, Craig M.; Fruman, David A.

doi:10.1172/jci77198

Cited by 15 publications

(14 citation statements)

References 20 publications

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“…The phenotype of activated PI3K-d syndrome (APDS) includes recurrent respiratory infections, severe viral infections, autoimmunity, lymphoproliferation/lymphoma and neurodevelopmental problems, accompanied by variable lymphopenia with increased circulating transitional B lymphocytes, increased IgM and impaired vaccine responses, and reduced naive and increased senescent T lymphocytes with reduced proliferative capacity. [1][2][3] Although variable in severity, it can present as or evolve into a profound combined immunodeficiency, justifying the consideration of hematopoetic stem cell transplantation (HSCT). We report the first series of HSCT in this disorder.…”

Section: Hematopoietic Stem Cell Transplant In Patients With Activatementioning

confidence: 99%

“…Lucas et al 4 Patients with APDS may benefit from rapamycin or other inhibitors of PI3K. 1,2,5 Despite reports of impressive responses, not all patients achieve durable disease remission. Chronic morbidity and death from severe infection and lymphoma are reported such that HSCT is a relevant consideration.…”

Section: Hematopoietic Stem Cell Transplant In Patients With Activatementioning

confidence: 99%

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Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome

Nademi

Slatter

Dvorak

et al. 2017

Journal of Allergy and Clinical Immunology

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Section: Hematopoietic Stem Cell Transplant In Patients With Activatementioning

confidence: 99%

Section: Hematopoietic Stem Cell Transplant In Patients With Activatementioning

confidence: 99%

Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome

Nademi

Slatter

Dvorak

et al. 2017

Journal of Allergy and Clinical Immunology

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“…Recently, 2 important articles approached the role of thymic B cells in murine models, using transfer experiments and deficient lines (eg, autoimmune regulator [Aire] knock-out animals). They demonstrated that murine thymic B cells are potent APCs to autoreactive T cells 2 and that they can harbor different self tissue-restricted antigens (TRAs) induced by Aire expression. 3 But only little is known about the fate and function of human B cells in thymus with mostly immunochemistry data.…”

Section: B Cells Differentiate In Human Thymus and Express Airementioning

confidence: 99%

B cells differentiate in human thymus and express AIRE

Gies

Guffroy

Danion

et al. 2017

Journal of Allergy and Clinical Immunology

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“…Higher steady-state levels of p-AKT are observed in vitro and ex vivo , indicating that the mutations are GOF. Thus, GOF mutations of PIK3R1 and PIK3CD seem to underlie immunological and clinical phenocopies [160,161]. PIK3R1 is more broadly expressed than PIK3CD.…”

Section: Infection With or Without Autoimmunity And Without Autoinflamentioning

confidence: 99%

Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind

Boisson

Quartier

Casanova

2015

Current Opinion in Immunology

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All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity.

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Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling

Abstract: C o m m e n t a r y 3 6 8 8

Cited by 15 publications

References 20 publications

Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome

Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome

B cells differentiate in human thymus and express AIRE

Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind

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