Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6

Barış, Safa; Benamar, Mehdi; Chen, Qian; Catak, Mehmet Cihangir; Martínez‐Blanco, Mónica; Wang, Muyun; Fong, Jason; Massaad, Michel J.; Sefer, Asena Pınar; Kara, Altan; Babayeva, Royala; Eltan, Sevgi Bilgiç; Yücelten, Ayşe Deniz; Bozkurtlar, Emine; Cinel, Leyla; Karakoç-Aydıner, Elif; Zheng, Yang; Wu, Hao; Özen, Ahmet; Schmitz-Abe, Klaus; Chatila, Talal

doi:10.1016/j.jaci.2023.01.023

Cited by 34 publications

(17 citation statements)

References 71 publications

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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%

“…These patients presented with early onset multiple severe food allergies and severe treatment resistant atopic dermatitis. Patients came to medical attention in the first year of life with asthma, gastrointestinal or skin eosinophilic infiltration, or severe anaphylactic reactions 59,120–122 . 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 .…”

Section: Stat6‐related Diseasementioning

confidence: 99%

“…Patients with STAT6 GOF were treated with a large number of immunosuppressive medications, such as systemic corticosteroids, methotrexate and mepolizumab without significant improvement in severe atopic disease prior to identification of the genetic underpinning of disease. Once STAT6 GOF mutations were identified, targeted therapy with JAK inhibitors, such as ruxolitinib and tofacitinib, as well as dupilumab, was initiated resulting in symptom control in the majority of patients 59,121 . Dupilumab, a monoclonal antibody that blocks IL‐4 and IL‐13, is FDA approved for the treatment of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis and eosinophilic esophagitis 60–62,123 .…”

Section: Stat6‐related Diseasementioning

confidence: 99%

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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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Section: Stat6 Gain Of Functionmentioning

confidence: 99%

Section: Stat6‐related Diseasementioning

confidence: 99%

Section: Stat6‐related Diseasementioning

confidence: 99%

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

Chaimowitz,

Smith,

Forbes Satter

2024

Immunological Reviews

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“…Most recently, heterozygous gain-of-function (GOF) variants in STAT6 have been found to cause a syndrome characterized by severe atopic disease (e.g., multiple food/drug allergies and dermatitis), eosinophilia, recurrent infections (mostly S. aureus, C. albicans, molluscum), and short stature. [144][145][146][147][148][149] In this setting, constitutive or prolonged STAT6 signaling downstream of IL-4 and IL-13 likely drives aberrant and excessive IgE production and overcomes any STAT3-mediated pathways that regulate class switching to and secretion of IgE.…”

Section: Immune Cells Ar Partial Lof or Heterozygous Dn Lof Variants ...mentioning

confidence: 99%

“…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%

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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JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences

et al. 2023

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The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway’s architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.

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Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6

Cited by 34 publications

References 71 publications

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

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

JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences

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