A germline STAT6 gain-of-function variant is associated with early-onset allergies

Suratannon, Narissara; Ittiwut, Chupong; Dik, Willem A.; Ittiwut, Rungnapa; Meesilpavikkai, Kornvalee; Israsena, Nipan; Ingrungruanglert, Praewphan; Dalm, Virgil A. S. H.; Daele, Paul LA. van; Sanpavat, Anapat; Chaijitraruch, Nataruks; Schrijver, Benjamin; Buranapraditkun, Supranee; Porntaveetus, Thantrira; Swagemakers, Sigrid; IJspeert, Hanna; Palaga, Tanapat; Suphapeetiporn, Kanya; Spek, Peter J. van der; Hirankarn, Nattiya; Chatchatee, Pantipa; Hagen, P M van; Shotelersuk, Vorasuk

doi:10.1016/j.jaci.2022.09.028

Cited by 26 publications

(19 citation statements)

References 21 publications

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“…The humans we identified with STAT6 GOF variants and STAT6VT mice share a number of key features of the allergic diathesis, including elevated serum IgE and chronic atopic dermatitis. Very recently, a report was published describing a father and his two sons with severe allergic disease who were all heterozygous for the GOF STAT6 variant p.E377K (Suratannon et al, 2022). This new family shares many of the features we report in our cohort of 10 families (Fig.…”

Section: Discussionsupporting

confidence: 72%

Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

Sharma

Leung

Momenilandi

et al. 2023

Journal of Experimental Medicine

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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

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Section: Discussionsupporting

confidence: 72%

Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

Sharma

Leung

Momenilandi

et al. 2023

Journal of Experimental Medicine

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“…Patients came to medical attention in the first year of life with asthma, gastrointestinal or skin eosinophilic infiltration, or severe anaphylactic reactions. 59,[120][121][122] Additional features of the disease also included recurrent skin and respiratory infections with bacteria, fungus or viruses, failure to thrive, skeletal hypermobility and pathologic fractures. 59 Immune testing demonstrated elevated IgE and peripheral eosinophilia while T cell, B cells and natural killer cell numbers were typically within the normal range.…”

Section: Stat6 Gain Of Functionmentioning

confidence: 99%

JAK/STAT defects and immune dysregulation, and guiding therapeutic choices

Chaimowitz,

Smith,

Forbes Satter

2024

Immunological Reviews

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SummaryInborn errors of immunity (IEIs) encompass a diverse spectrum of genetic disorders that disrupt the intricate mechanisms of the immune system, leading to a variety of clinical manifestations. Traditionally associated with an increased susceptibility to recurrent infections, IEIs have unveiled a broader clinical landscape, encompassing immune dysregulation disorders characterized by autoimmunity, severe allergy, lymphoproliferation, and even malignancy. This review delves into the intricate interplay between IEIs and the JAK–STAT signaling pathway, a critical regulator of immune homeostasis. Mutations within this pathway can lead to a wide array of clinical presentations, even within the same gene. This heterogeneity poses a significant challenge, necessitating individually tailored therapeutic approaches to effectively manage the diverse manifestations of these disorders. Additionally, JAK–STAT pathway defects can lead to simultaneous susceptibility to both infection and immune dysregulation. JAK inhibitors, with their ability to suppress JAK–STAT signaling, have emerged as powerful tools in controlling immune dysregulation. However, questions remain regarding the optimal selection and dosing regimens for each specific condition. Hematopoietic stem cell transplantation (HSCT) holds promise as a curative therapy for many JAK–STAT pathway disorders, but this procedure carries significant risks. The use of JAK inhibitors as a bridge to HSCT has been proposed as a potential strategy to mitigate these risks.

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“…Core clinical presentations associated with STAT6 GOF are early onset, severe allergic immune dysregulation including atopic dermatitis, multiple allergies and serial anaphylaxis, hypereosinophilia, and high serum IgE levels (>5000 U/mL). [144][145][146][147][148][149]217 Thus, IEI causing STAT6 GOF establishes that STAT6 activation, downstream of IL-4 and IL-13, is the central driver of IgE production by human B cells. [144][145][146][147][148][149]217 It remains to be determined how or whether IL-6/ STAT3 signaling directly or indirectly antagonizes IL-4:IL-13/STAT6 signaling in B cells to rein in IgE production.…”

Section: Stat6mentioning

confidence: 99%

“…[144][145][146][147][148][149]217 Thus, IEI causing STAT6 GOF establishes that STAT6 activation, downstream of IL-4 and IL-13, is the central driver of IgE production by human B cells. [144][145][146][147][148][149]217 It remains to be determined how or whether IL-6/ STAT3 signaling directly or indirectly antagonizes IL-4:IL-13/STAT6 signaling in B cells to rein in IgE production. The availability of material from patients with common clinical features of IgE dysregulation but distinct genetic etiologies provide opportunities to dissect the cellular, biochemical, and molecular pathways responsible for controlling IgE production to ensure sufficient IgE-mediated protection against parasitic infections but also prevent IgE-mediated atopic pathologies.…”

Section: Stat6mentioning

confidence: 99%

The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

Tangye,

Mackie,

Pathmanandavel

et al. 2023

Immunological Reviews

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SummaryThe essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)‐secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high‐affinity Ag‐specific Abs of different classes, enabling effective pathogen neutralization and long‐lived humoral immunity. However, perturbations to these key signaling pathways underpin immune dyscrasias including immune deficiency and autoimmunity or allergy. Inborn errors of immunity that disrupt critical immune pathways have identified non‐redundant requirements for eliciting and maintaining humoral immune memory but concomitantly prevent immune dysregulation. Here, we will discuss our studies on human B cells, and how our investigation of cytokine signaling in B cells have identified fundamental requirements for memory B‐cell formation, Ab production as well as regulating Ig class switching in the context of protective versus allergic immune responses.

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A germline STAT6 gain-of-function variant is associated with early-onset allergies

Cited by 26 publications

References 21 publications

Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

JAK/STAT defects and immune dysregulation, and guiding therapeutic choices

The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

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