ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans

Lyons, Jonathan J.; Y, Liu; Ca, Ma; Yu, Xinmin; O’Connell, Michael P.; Mg, Lawrence; Zhang, Yuan; Karpe, Kendal A.; Zhao, Ming; Am, Siegel; Kd, Stone; Nelson, Celeste; Jones, Nina; DiMaggio, Tom; Dn, Darnell; Mendoza-Caamal, Elvia; Orozco, Lorena; Jd, Hughes; McElwee, Joshua; Rj, Hohman; Pa, Frischmeyer-Guerrerio; Me, Rothenberg; Af, Freeman; Holland, SM; Jd, Milner

doi:10.1084/jem.20161435

Cited by 74 publications

(51 citation statements)

References 48 publications

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“…The discovery of defective Th17 cell differentiation in patients with this syndrome [71-75], together with inborn errors of IL-12Rβ1, IL-17A/F, and the IL-17RA/IL-17RC receptor complex, RORC, and ACT1 [97-107], strongly suggested that IL-17 activity played a key role in attracting neutrophils to the tissues and controlling mucocutaneous fungal infections [97, 99]. The recent discovery of an ERBIN-deficient family has bridged the gap between STAT3 and TGF-β signaling [108]. STAT3 promotes the expression of ERBIN, which impairs TGF-β signaling, thereby skewing CD4 + T-cell differentiation and impairing Treg functions.…”

Section: Job’s Syndromementioning

confidence: 99%

Human hyper-IgE syndrome: singular or plural?

et al. 2018

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Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50 years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term "HIES" to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

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Section: Job’s Syndromementioning

confidence: 99%

Human hyper-IgE syndrome: singular or plural?

et al. 2018

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“…ERBB2‐interacting protein (ERBIN) is integral for STAT3‐mediated downregulation of TGF‐β signalling. Loss of ERBIN favours regulatory T‐cell (T‐reg) and Th2 polarization, recapitulating the allergic and connective tissue phenotypes of LDS and STAT3‐HIES . Homozygous mutation of IL6ST (encoding GP130) has recently been described in a patient presenting with eczema, recurrent infections, bronchiectasis, high IgE, defective B‐cell memory.…”

Section: Iii: Syndromic Appearance or Connective Tissue Disordermentioning

confidence: 99%

Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

Ponsford¹,

Klocperk

Pulvirenti

et al. 2018

Allergy

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The 2017 International Union of Immunological Societies (IUIS) classification recognizes 3 hyper-IgE syndromes (HIES), including the prototypic Job's syndrome (autosomal dominant STAT3-loss of function) and autosomal recessive PGM3 and SPINK5 syndromes. Early diagnosis of PID can direct life-saving or transformational interventions; however, it remains challenging owing to the rarity of these conditions. This can result in diagnostic delay and worsen prognosis. Within increasing access to "clinical-exome" testing, clinicians need to be aware of the implication and rationale for genetic testing, including the benefits and limitations of current therapies. Extreme elevation of serum IgE has been associated with a growing number of PID syndromes including the novel CARD11 and ZNF341 deficiencies. Variable elevations in IgE are associated with defects in innate, humoral, cellular and combined immunodeficiency syndromes. Barrier compromise can closely phenocopy these conditions. The aim of this article was to update readers on recent developments at this important interface between allergy and immunodeficiency, highlighting key clinical scenarios which should draw attention to possible immunodeficiency associated with extreme elevation of IgE, and outline initial laboratory assessment and management.

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“…62e65 Additional evidence implicating the TGF-b pathway as important in EoE comes from recent studies demonstrating that STAT3 negatively regulates TGF-b signaling via ERBB2interacting protein, an SMAD anchor for receptor activation. 66 This mechanism is clinically significant, because individuals with dominant-negative STAT3 mutations (autosomal dominant hyper-IgE syndrome) have increased incidence of EoE. 67 Therefore, some evidence suggests that a predisposition to develop fibrosis may be at the basis of the EoE fibrostenotic phenotype.…”

Section: Genotype Correlations In Eoementioning

confidence: 99%

Phenotypes and endotypes in eosinophilic esophagitis

Ruffner

Cianferoni

2020

Annals of Allergy, Asthma & Immunology

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Eosinophilic esophagitis (EoE) shares many features with other atopic diseases such as asthma, including heterogeneity in its presentation, natural history, and response to treatment. Clinical and molecular evidence suggests that different eosinophilic esophagitis patient phenotypes and endotypes exist. Phenotypic variations in EoE include the age of onset, degree of atopic comorbidity, response to different forms of therapy, and disease severity, among others. Biomarkers that may provide insight into the mechanisms of EoE for defining endotypes include the presence or absence of systemic Th2 inflammation, genetic risk factors, and histologic findings.

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ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans

Abstract: Lyons et al. show that STAT3 negatively regulates TGF-β signaling via ERBIN and that cell-intrinsic deregulation of TGF-β pathway activation promotes the IL-4/IL-4Rα/GATA3 axis to support atopic phenotypes in humans.

Cited by 74 publications

References 48 publications

Human hyper-IgE syndrome: singular or plural?

Human hyper-IgE syndrome: singular or plural?

Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

Phenotypes and endotypes in eosinophilic esophagitis

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