Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea

Chi, Aiping; Xi, Liqiang; Cauff, Brian; DeZure, Adam; Freeman, Alexandra F.; Hambleton, Sophie; Kleiner, Gary; Leahy, T. Ronan; O’Sullivan, Maureen; Makiya, Michelle; O’Regan, Gráinne M.; Pittaluga, Stefania; Niemela, Julie E.; Stoddard, Jennifer; Rosenzweig, Sergio D.; Raffeld, Mark; Klion, Amy D.; Milner, Joshua D.

doi:10.1182/blood-2016-09-737817

Cited by 82 publications

(41 citation statements)

References 13 publications

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“…17,23 It is important to distinguish from the somatic mutations in STAT5B associated with lymphocytic leukemia, 55 as well as the recently characterized novel variant N642H gainof-function mutation shown to be associated with eosinophilia, urticaria, dermatitis, and diarrhea. 55,56 The homozygous mutation identified in our patients was a deletion of a single G at the junction of exon 13-intron 13, 36 which affects the expression of STAT5b in PBMCs and BLCL cells but not STAT5a. The STAT5b-deficient siblings included in this study had significantly reduced NK cells in the periphery.…”

Section: Discussionmentioning

confidence: 82%

Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function

Vargas-Hernández

Witalisz-Siepracka

Prchal-Murphy

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: Patients with signal transducer and activator of transcription 5b (STAT5b) deficiency have impairment in T-cell homeostasis and natural killer (NK) cells which leads to autoimmunity, recurrent infections, and combined immune deficiency. Objective: In this study we characterized the NK cell defect in STAT5b-deficient human NK cells, as well as Stat5b 2/2 mice. Methods: We used multiparametric flow cytometry, functional NK cell assays, microscopy, and a Stat5b 2/2 mouse model to elucidate the effect of impaired and/or absent STAT5b on NK cell development and function. Results: This alteration generated a nonfunctional CD56 bright NK cell subset characterized by low cytokine production. The CD56 dim NK cell subset had decreased expression of perforin and CD16 and a greater frequency of cells expressing markers of immature NK cells. We observed low NK cell numbers and impaired NK cell maturation, suggesting that STAT5b is involved in terminal NK cell maturation in Stat5b 2/2 mice.

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Section: Discussionmentioning

confidence: 82%

Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function

Vargas-Hernández

Witalisz-Siepracka

Prchal-Murphy

et al. 2020

Journal of Allergy and Clinical Immunology

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“…Seemingly paradoxically, excessive STAT5 signaling has also been shown to cause allergic and myeloproliferative phenotypes in mouse models . However, these findings correlate with the report of a somatic heterozygous gain‐of‐function STAT5B ( STAT5B GOF ) mutation in two unrelated children who presented with severe atopic dermatitis, evidence of autoimmunity, marked eosinophilia with gut infiltration and diarrhea, food allergy, and urticaria beginning in childhood; short stature was reported in one of the two individuals; this mutation had previously been reported only in association with leukemia or lymphoma …”

Section: Allergic Disease a Growing Problemmentioning

confidence: 52%

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

Lyons

Milner

2018

Immunological Reviews

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Summary Dynamic changes in metabolism have long been understood as critical for both the initiation and maintenance of innate and adaptive immune responses. A number of recent advances have clarified details of how metabolic pathways can specifically affect cellular function in immune cells. Critical to this understanding is ongoing study of the congenital disorders of glycosylation and other genetic disorders of metabolism that lead to altered immune function in humans. While there are a number of immune phenotypes associated with metabolic derangements caused by single gene disorders, several genetic mutations have begun to link discrete alterations in metabolism and growth specifically with allergic disease. This subset of primary atopic disorders is of particular interest as they illuminate how hypomorphic mutations which allow for some residual function of mutated protein products permit the “abnormal” allergic response. This review will highlight how mutations altering sugar metabolism and mTOR activation place similar constraints on T lymphocyte metabolism to engender atopy, and how alterations in JAK/STAT signaling can impair growth and cellular metabolism while concomitantly promoting allergic diseases and reactions in humans.

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“…In murine models, the increased activity of STAT3 causes an increase in the sensitivity of IL-3 and an increase in the production of thymic stromal lymphopoietin, which may explain dermatitis-like manifestations. The manifestations do not have a good response with conventional treatment and hematopoietic progenitor cell transplantation has been performed although with post-transplant complications [51].…”

Section: Hypereosinophilic Syndrome Due To Somatic Mutations In Stat5bmentioning

confidence: 99%

Phenocopies: Mimics of Inborn Errors of Immunity

Alonso-Bello¹,

Espinosa‐Padilla²,

Temix-Delfin³

et al. 2020

OALib

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A phenocopy is defined as a clinical non-inherited phenotype in an individual, with environmental induction, which is identical to the genetically determined phenotype of another. Until February 2017, the IUIS (International Union of Immunological Societies) reported in its classification 354 innate immunity errors and a final group (classification table IX) with conditions that are not part of the innate alterations and are called phenocopies. These are classified into two types, the associated with somatic mutations and those associated with auto-antibodies. The phenotypes that occur by any of the mechanisms mentioned are complex and varied. It is necessary to know the clinical manifestations of the pathologies classified in this group to enrich the possible differential diagnoses in individuals with suspected immunodeficiency.

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Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea

Cited by 82 publications

References 13 publications

Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function

Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

Phenocopies: Mimics of Inborn Errors of Immunity

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