Search

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward T H 2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with T H 2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity cover a broad spectrum of diseases from immune deficiency syndromes to hyperinflammatory conditions. Primary atopic disorders are a recent member of this spectrum as a group that embracing monogenic immune deregulatory diseases causing allergic and atopic phenotypes. Liable genetic alterations lead to signaling pathways and cellular functioning changes, which skew to type-2 immune responses. Elucidation of these pathways and identifying these disorders have the utmost importance, since early identification of some of these disorders significantly changes the prognosis and targeted treatments offer improved outcomes. In this review, these broad-spectrum of diseases including recent findings were categorized and affected pathways and clinical phenotypes were explained.

Inborn errors of immunity cover a broad spectrum of diseases from immune deficiency syndromes to hyperinflammatory conditions. Primary atopic disorders are a recent member of this spectrum as a group that embracing monogenic immune deregulatory diseases causing allergic and atopic phenotypes. Liable genetic alterations lead to signaling pathways and cellular functioning changes, which skew to type-2 immune responses. Elucidation of these pathways and identifying these disorders have the utmost importance, since early identification of some of these disorders significantly changes the prognosis and targeted treatments offer improved outcomes. In this review, these broad-spectrum of diseases including recent findings were categorized and affected pathways and clinical phenotypes were explained. [ABSTRACT FROM AUTHOR]

Transcription factors (TFs) are critical components involved in regulating immune system development, maintenance, and function. Monogenic defects in certain TFs can therefore give rise to inborn errors of immunity (IEIs) with profound clinical implications ranging from infections, malignancy, and in some cases severe allergic inflammation. This review examines TF defects underlying IEIs with severe atopy as a defining clinical phenotype, including STAT3 loss-of-function, STAT6 gain-of-function, FOXP3 deficiency, and T-bet deficiency. These disorders offer valuable insights into the pathophysiology of allergic inflammation, expanding our understanding of both rare monogenic and common polygenic allergic diseases. Advances in genetic testing will likely uncover new IEIs associated with atopy, enriching our understanding of molecular pathways involved in allergic inflammation. Identification of monogenic disorders profoundly influences patient prognosis, treatment planning, and genetic counseling. Hence, the consideration of IEIs is essential for patients with severe, early-onset atopy. This review highlights the need for continued investigation into TF defects to enhance our understanding and management of allergic diseases.

Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy‐related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper‐IgE syndromes, Omenn syndrome, Wiskott‐Aldrich syndrome, IPEX‐linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement. [ABSTRACT FROM AUTHOR]

B-cell lymphoma/leukemia 11B (BCL11B) is a C2H2 zinc finger transcription factor that is critically important for regulating the development and function of a variety of systems including the central nervous system, the skin, and the immune system. Germline heterozygous variants are associated with a spectrum of clinical disorders, including severe combined immunodeficiency as well as neurological, craniofacial, and dermal defects. Of these individuals, ~50% present with severe allergic disease. Here, we report the detailed clinical and laboratory workup of one of the most severe BCL11B-dependent atopic cases to date. Leveraging a zebrafish model, we were able to confirm a strong T-cell defect in the patient. Based on these data, we classify germline BCL11B-dependent atopic disease as a novel primary atopic disorder.

B-cell lymphoma/leukemia 11B (BCL11B) is a C2H2 zinc finger transcription factor that is critically important for regulating the development and function of a variety of systems including the central nervous system, the skin, and the immune system. Germline heterozygous variants are associated with a spectrum of clinical disorders, including severe combined immunodeficiency as well as neurological, craniofacial, and dermal defects. Of these individuals, ~50% present with severe allergic disease. Here, we report the detailed clinical and laboratory workup of one of the most severe BCL11B-dependent atopic cases to date. Leveraging a zebrafish model, we were able to confirm a strong T-cell defect in the patient. Based on these data, we classify germline BCL11B-dependent atopic disease as a novel primary atopic disorder. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity are traditionally best known for enhancing susceptibility to infections. However, allergic inflammation, among other types of immune dysregulation, occurs frequently in patients with inborn errors of immunity. As such, the term primary atopic disorders (PADs) was recently coined to describe the group of heritable monogenic allergic disorders. It is becoming increasingly important for clinicians to recognize that allergic diseases such as food allergy, atopic dermatitis, and allergic asthma are expressions of misdirected immunity, and in patients who present with severe, early-onset, or coexisting allergic conditions, these can be indications of an underlying PAD. Identifying monogenic allergic disease through next-generation sequencing can dramatically improve outcomes by allowing the use of precision-based therapy targeting the patient's underlying molecular defect. It is therefore imperative that clinicians recognize PADs to be able to provide informed therapeutic options and improve patient outcomes. Here, we summarize the clinical features commonly seen with each of the currently known PADs, identify clinical warning signs that warrant assessment for PADs, and lastly, discuss the benefits of timely diagnosis and management of these conditions. [ABSTRACT FROM AUTHOR]

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward T H 2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with T H 2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations., Competing Interests: Disclosure statement This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Disclosure of potential conflict of interest: J. D. Milner served on the scientific advisory board for Blueprint Medicine. The rest of the authors declare that they have no relevant conflicts of interest., (Published by Elsevier Inc.)

Primary atopic disorders describes a series of monogenic diseases that have allergy- or atopic effector–related symptoms as a substantial feature. The underlying pathogenic genetic lesions help illustrate fundamental pathways in atopy, opening up diagnostic and therapeutic options for further study in those patients, but ultimately for common allergic diseases as well. Key pathways affected in these disorders include T cell receptor and B cell receptor signaling, cytokine signaling, skin barrier function, and mast cell function, as well as pathways that have not yet been elucidated. While comorbidities such as classically syndromic presentation or immune deficiency are often present, in some cases allergy alone is the presenting symptom, suggesting that commonly encountered allergic diseases exist on a spectrum of monogenic and complex genetic etiologies that are impacted by environmental risk factors. [ABSTRACT FROM AUTHOR]

[Display omitted] Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased T H 2- and suppressed T H 1- and T H 17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized T H 1 and T H 17 cells, suppressed the eosinophilia, and improved the patient's atopic dermatitis. This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder. [ABSTRACT FROM AUTHOR]

Allergic diseases were long considered to be complex multifactorial disorders. However, recent findings indicate that severe allergic inflammation can be caused by monogenic immune defects. We sought to clarify the molecular pathogenesis of a patient with early-onset multiple allergic diseases, a high serum IgE level, hypereosinophilia, treatment-resistant severe atopic dermatitis with increased dermal collagen fiber deposition, and eosinophilic gastrointestinal disorder with numerous polypoid nodules. A missense variant in STAT6 was identified, and its function was examined using peripheral blood, transfected HEK293 cells, lymphoblastoid cell lines, and knock-in mice with the corresponding mutation. Whole-exome sequencing identified a de novo heterozygous missense variant in signal transducer and activator of transcription 6 (STAT6) (p.Asp419Asn). Luciferase reporter assay revealed that the transcriptional activity of this STAT6 mutant was upregulated even without IL-4 stimulation. Phosphorylation of STAT6 was not observed in either the patient's T H 2 cells or lymphoblastoid cell lines without stimulation, whereas it was induced more strongly in both by IL-4 stimulation compared with healthy controls. STAT6 protein was present in the nuclear fraction of the lymphoblastoid cell lines of the patient even in the absence of IL-4 stimulation. The patient's gastric mucosa showed upregulation of STAT6-, fibrosis-, and germinal center formation–related molecules. Some of the knock-in mice with the corresponding mutation spontaneously developed dermatitis with skin thickening and eosinophil infiltration. Moreover, serum IgE levels and mRNA expression of type 2 cytokines were increased in the knock-in mice—with or without development of spontaneous dermatitis—compared with the wild-type mice. A novel STAT6 gain-of-function variant is a potential cause of primary atopic disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 gain-of-function variants leading to allergies in humans. We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members. Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines. We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient's father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood T H 2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules. A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Allergic diseases are a heterogeneous group of disorders resulting from exaggerated type 2 inflammation. Although typically viewed as polygenic multifactorial disorders caused by the interaction of several genes with the environment, we have come to appreciate that allergic diseases can also be caused by monogenic variants affecting the immune system and the skin epithelial barrier. Through a myriad of genetic association studies and high-throughput sequencing tools, many monogenic and polygenic culprits of allergic diseases have been described. Identifying the genetic causes of atopy has shaped our understanding of how these conditions occur and how they may be treated and even prevented. Precision diagnostic tools and therapies that address the specific molecular pathways implicated in allergic inflammation provide exciting opportunities to improve our care for patients across the field of allergy and immunology. Here, we highlight offender genes implicated in polygenic and monogenic allergic diseases and list targeted therapeutic approaches that address these disrupted pathways., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)