RARE DISEASE
Hyper-IgE syndrome
Hyper-IgE syndrome
Hyper-IgE syndrome
Drug discovery
1
drug
With orphan designation
Overview
Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin and lung infections, eczema, and elevated serum IgE levels (>2000 IU/mL). Most cases arise from STAT3 (autosomal dominant) or DOCK8 (autosomal recessive) mutations, impairing Th17 differentiation and immune regulation. Clinical features include cold abscesses, pneumatoceles, skeletal/dental anomalies, and increased malignancy risk. Chronic infections drive morbidity, necessitating lifelong multidisciplinary management [1][6][11][17].
Burden
High morbidity from recurrent infections (20% develop pneumatoceles) and secondary lung damage [1][6][19].
Malignancy risk: 6.5% lifetime prevalence (lymphomas, SCC) [4][11][17].
Reduced quality of life due to chronic symptoms, frequent hospitalizations, and complications like fractures/scoliosis [9][16][17].
Therapies
Prophylaxis: Daily antistaphylococcal antibiotics (e.g., TMP-SMX), antifungals, and antivirals [1][11][16].
Biologics: Omalizumab (anti-IgE) for asthma/allergic components; dupilumab (IL-4/13 inhibitor) for refractory eczema [3][8][11].
Curative: Hematopoietic stem cell transplant for DOCK8 deficiency [1][14].
Categories: rare genetic diseases, rare immunological diseases
Research Papers
381 drug discovery papers about Hyper-IgE syndrome, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
381 drug discovery papers about Hyper-IgE syndrome, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-04-13 | Dock8 regulates Th2 cell differentiation through ANXA1.
Dedicator of Cytokinesis 8 (DOCK8), a member of the DOCK family of guanine nucleotide exchange factors, serves as a key factor in managing the Rho GTPases activity, notably Cdc42 and Rac1, which control key cellular processes, including migration, adhesion, and phagocytosis. Mutations in the DOCK8 gene cause autosomal recessive hyper-IgE syndrome (AR-HIES), a primary immunodeficiency disorder characterized by elevated serum IgE levels, eczema, recurrent infections, and defective immune responses. In this study, a CRISPR/Cas9-generated Dock81281&1282 TG deletion mutation mouse model was constructed to investigate the immunological consequences of Dock8 deficiency. Our results demonstrate that Dock8 is essential for the peripheral homeostasis of T cells, particularly T follicular helper (Tfh), Th2, and regulatory T cells (Treg). Notably, in Dock8 mutant mice, both Th2 and Tfh cells were elevated, and they collaboratively promote IgE production. Additionally, we identified that Annexin A1 (ANXA1) enhances Th2 cell differentiation in Dock8 mutants, suggesting its potential role in restoring immune balance. These findings provide a refined understanding of the molecular mechanisms associated with DOCK8-related immune deficiencies and highlight potential therapeutic strategies for managing AR-HIES.
2025-12-09 | Successful Interferon-α Therapy for a Huge Lesion Including Eye and Eyelids
Introduction Defective T cell responses lead to insufficient interferon production, thereby compromising antiviral immunity and increasing vulnerability to viral infections in combined immunodeficiency disorders. The DOCK8 deficiency, also known as autosomal recessive (AR) hyper IgE syndrome (HIES), is a combined immunodeficiency characterized by susceptibility to eczema, respiratory tract infections, allergies, malignancies, autoimmunity, and cutaneous viral infections caused by herpes simplex virus, pox virus, human papillomavirus, molluscum contagiosum virus, and orf virus, along with elevated serum IgE levels and hypereosinophilia (Goker E et al., Pediatr Allergy Immunol 2022; 33: e13666). DOCK8 encodes a guanine nucleotide exchange factor that regulates the actin cytoskeletonʼs response to mitogenic and chemokine signals via the reversible activation of small G proteins, including cell division cycle 42 (Harada Y et al., Blood 2012; 119: 4451–4461). DOCK8 deficiency affects the migration, function, and viability of both innate and adaptive immune cells. The memory compartments of T and B cells, lymphoproliferation in response to mitogens, T cell migration, and NK cell cytotoxicity are predominantly diminished (Zhang Q et al., N Engl J Med 2009; 361: 2046–2055). Patients with DOCK8 deficiency suffer persistent cutaneous viral infections, potentially due to compromised actin cytoskeleton responses, which are crucial for immune cell migration to infection sites, and a reduction in plasmacytoid dendritic cells (pDC) that secrete essential type 1 interferons for viral clearance (Mizesko M et al., J Allergy Clin Immunol 2013; 131: 840–848). Type I interferons (IFNs) upregulate the expression of major histocompatibility complex molecules I and II, enhancing the presentation of viral peptides to cytotoxic T cells through conventional DCs, as well advocating NK functions. Both non-pegylated and pegylated IFN-α (PEG IFN-a) were used successful for difficult-to-treat cutaneous viral infections in a few patients with HIES (Al-Zahrani D et al., Clin Immunol 2014; 153: 104–108; Papan C et al., J Allergy Clin Immunol 2014; 133: 1456–1458; Kilic S et al., Pediatrics 2006; 117: e1253–e1255; Benninghoff U et al., Pediatr Allergy Immunol 2008; 19: 564–568). Publication History Received: 22 May 2025 Accepted after revision: 05 November 2025 Article published online: 09 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-12-08 | Environmental exposures, epithelial barrier dysfunction, and the evolving landscape of allergic disorders and asthma.
Immediate hypersensitivity disorders, such as asthma, food intolerance, and anaphylaxis, have risen dramatically since the 20th century, marking a shift in the global disease burden. While mast cells have been associated with IgE-mediated disorders, they also play important roles in homeostasis. To prevent chronic inflammation and aberrant tissue remodeling, tight regulation of mast cells is essential in response to microorganisms, autoantigens, and environmental changes. The surge in mast cell-mediated disorders and evidence of mast cell interactions with epithelial and neural networks have led to the epithelial barrier hypothesis. This hypothesis extends the protective role of the epithelium by highlighting its integrated communication with both the nervous and immune systems, proposing that dysregulated nerve-mast cell signaling at epithelial barriers contributes to the development of immediate hypersensitivity disorders - both allergic and nonallergic phenotypes. In turn, it offers new strategies for prevention and treatment, focusing on restoring barrier integrity and modulating neuroimmune pathways. Clinical populations including hypermobility syndromes, such as certain Ehlers-Danlos syndrome variants and Job syndrome, exemplify the systemic consequences of disrupted epithelial barriers and chronic nerve-mast cell dysregulation. Accordingly, this review discusses the co-emergence of hypersensitivity and hypermobility syndromes as manifestations of immune-neuro-epithelial dysfunction in the context of modern environmental change.
2024-07-21 | Allergic fungal rhinosinusitis linked to other hyper-IgE syndromes through defective TH17 responses.
In a gene expression analysis comparing sinus mucosa samples from allergic fungal rhinosinusitis (AFRS) patients with samples from non-AFRS chronic rhinosinusitis with nasal polyp (CRSwNP) patients, the antimicrobial peptide (AMP) histatin 1 (HTN1) was found to be the most differentially downregulated gene in AFRS. We sought to identify the molecular etiology of the downregulated expression of HTN1. We used RT-PCR to compare the expression of AMPs and a fungistasis assay to evaluate the antifungal activity of sinus secretions. Using flow cytometry, we characterized the presence of TH17/TH22 cells and signal transducer and activator of transcription (STAT) signaling from AFRS patients, non-AFRS CRSwNP patients, and healthy controls. We confirmed decreased expression of AMPs in AFRS sinus mucosa with concordant decrease in antifungal activity in sinus secretions. IL-22 and IL-22-producing T cells were deficient within sinus mucosa of AFRS patients. In vitro studies demonstrated a defect in IL-6/STAT3 signaling critical for TH17/TH22 differentiation. Epithelial cells from AFRS patients could express AMPs when stimulated with exogenous IL-22/IL-17 and circulating TH17 cell abundance was normal. Similar to other hyper-IgE syndromes, but distinct from CRSwNP, AFRS patients express a defect in STAT3 activation limited to IL-6-dependent STAT3 phosphorylation that is critical for TH17/TH22 differentiation. This defect leads to a local deficiency of IL-17/IL-22 cytokines and deficient AMP expression within diseased sinus mucosa of AFRS patients. Our findings support evaluation of therapeutic approaches that enhance airway AMP production in AFRS.
2024-06-17 | Extracellular Vesicles based STAT3 delivery as innovative therapeutic approach to restore STAT3 signaling deficiency.
Extracellular Vesicles (EVs) have been proposed as a promising tool for drug delivery because of their natural ability to cross biological barriers, protect their cargo, and target specific cells. Moreover, EVs are not recognized by the immune system as foreign, reducing the risk of an immune response and enhancing biocompatibility. Herein, we proposed an alternative therapeutic strategy to restore STAT3 signaling exploiting STAT3 loaded EVs. This approach could be useful in the treatment of Autosomal Dominant Hyper-IgE Syndrome (AD-HIES), a rare primary immunodeficiency and multisystem disorder due to the presence of mutations in STAT3 gene. These mutations alter the signal transduction of STAT3, thereby impeding Th17 CD4+ cell differentiation that leads to the failure of immune response. We set up a simple and versatile method in which EVs were loaded with fully functional STAT3 protein. Moreover, our method allows to follow the uptake of STAT3 loaded vesicles inside cells due to the presence of EGFP in the EGFP-STAT3 fusion protein construct. Taken together, the data presented in this study could provide the scientific background for the development of new therapeutic strategy aimed to restore STAT3 signaling in STAT3 misfunction associated diseases like AD-HIES. In the future, the administration of fully functional wild type STAT3 to CD4+ T cells of AD-HIES patients might compensate its loss of function and would be beneficial for these patients, lowering the risk of infections, the use of medications, and hospitalizations.
small molecules
2026-07-20 | The V3 Phase Architecture Applied to the Entire Human Humoral Immune System: A Complete, Certifiable Ada/SPARK Framework Simulating the Assembly of All Four Immunoglobulin Isotypes (IgM, IgG, IgA, IgE) with Pathological Stress Testing Across 10 Immunological Diseases — Validated by Inverse Invariant Collapse and GNATprove 100%
s ABSTRACT: Background & Biological Hypothesis: Classical immunology often views humoral immunodeficiencies, autoimmune disorders, and hypersensitivity reactions as isolated biochemical anomalies governed by complex molecular cascades. This study provides formal proof for a novel biophysical paradigm: human humoral immunity functions as a unified phase-equilibrium system governed by deterministic biophysical invariants (V3 energy invariant Ψ_V3 = 48,016.8 kg/m² and critical bioelectric potential Φ_critical = -51.1 mV). Within this framework, biological health is defined as structural phase stability, whereas immune pathologies represent predictable, threshold-driven phase ruptures. Biological Proof & Mechanistic Discovery: Through high-integrity computational modeling of all four major immunoglobulin classes (IgM, IgG, IgA, IgE), we demonstrate that specific immunopathologies do not occur randomly, but are triggered precisely when individual biophysical parameters cross non-negotiable physical thresholds: • IgM & Assembly Topology: Pentameric IgM integrity requires strict k = 7 heptadic closure via the J-chain. We prove that a drop below k = 5 prevents ring closure, dumping truncated monomers into the bloodstream and causing Waldenström macroglobulinemia. Furthermore, an bioelectric potential shift above Φ > -40.0 mV disrupts polypeptide folding energy, triggering Selective IgM Deficiency, while loss of vesicular transport coherence (< 50%) leads to Hyper-IgM Syndrome. • IgG & Structural Flexibility: Proper H2L2 domain folding coherence is required for secretable IgG; falling below 60% coherence triggers endo-reticular degradation, causing Hypogammaglobulinemia. Hinge region destabilization below 70% impairs receptor binding dynamics, causing Myasthenia Gravis, while endosomal pH-FcRn gradient disruption halts maternal-fetal transfer, driving Hemolytic Disease of the Fetus and Newborn (HDFN). • IgA & Mucosal Shielding: Mucosal protection strictly depends on the presence of the Secretory Component (SC); its absence completely strips mucosal immunity, resulting in Selective IgA Deficiency. Additionally, hinge O-glycosylation below an 80% threshold alters protein solubility, proving that IgA Nephropathy (Berger’s Disease) is driven by threshold-dependent glomerular self-aggregation. • IgE & Allergic Signaling: IgE over-coherence (> 90%) drives unchecked production seen in Hyper-IgE (Job's) Syndrome. Conversely, when allergen-mediated FcεRI crosslinking density exceeds 30%, the mast-cell membrane equilibrium collapses instantly, releasing massive histamine surges in Anaphylactic Shock. Significance for Immunology: This work formally proves that immunological diseases are quantifiable physical phase ruptures. By mapping ten distinct clinical conditions to exact mathematical thresholds, the V3 framework demonstrates that humoral pathologies share a single universal law of phase rupture. This transforms clinical immunology from a descriptive science into a predictive, deterministic biophysical discipline, offering a new foundation for therapeutic target design and precision immunotherapeutics.
2026-06-17 | [Guillain-Barré syndrome following allogeneic hematopoietic stem cell transplantation in a pediatric patient: a case report and literature review].
A 10-year-old girl diagnosed with hyper-IgE syndrome for more than six years developed dizziness and symmetrical progressive limb weakness one week prior to hospital admission, occurring 4 months after allogeneic hematopoietic stem cell transplantation. On post-transplant day 121, dizziness and progressive, symmetric limb weakness appeared. Cerebrospinal fluid analysis revealed albuminocytologic dissociation. Electromyography confirmed multiple peripheral nerve lesions, consistent with the diagnosis of Guillain-Barré syndrome. Intravenous immunoglobulin therapy showed limited efficacy, whereas corticosteroid therapy produced significant clinical improvement. Neurological symptoms fully resolved after treatment; however, severe chronic graft-versus-host disease occurred subsequently. Based on this case, related literature was reviewed and summarized to provide references for early diagnosis, mechanistic investigation, and treatment options.
2026-05-10 | Tofacitinib as a Successful Treatment for Hyper-IgE Syndrome and Autoimmunity Associated with Constitutive Activation of JAK3.
The Janus Kinase 3 (JAK3) germline gain-of-function (GOF) mutation is a rare inborn error of immunity, first reported in 2020, characterized by lymphopenia and chronic NK-cell proliferation. However, its role in autoimmunity remains unclear, and no direct association with hyper-IgE syndrome (HIES) has been established. In this study, we describe a patient presenting with HIES, myositis, lymphopenia, and autoimmune hypothyroidism. Whole-exome sequencing identified a novel compound heterozygous JAK3 mutation (c.2524_2525delinsTT and c.2805G > C), predicted to be deleterious. Flow cytometry and RNA sequencing of peripheral blood mononuclear cells revealed a significant reduction in T cells and NK cells, particularly naïve CD4+ T cells, accompanied by a marked imbalance in T cell subsets. This led to constitutive activation of JAK1 and JAK3, along with increased STAT3 and STAT5 phosphorylation. Tofacitinib treatment significantly improved the patient's symptoms. Our findings expand the clinical spectrum of JAK3-associated immune dysregulation, linking it for the first time to HIES and multiple autoimmune manifestations. Furthermore, this study suggests that tofacitinib may be a potential therapeutic option for JAK3 signaling-associated immune dysregulation.
2026-05-01 | Coronary Artery Dilation and Tortuosity in STAT3DN Hyper IgE Syndrome
Background Hyper IgE syndrome from dominant-negative STAT3 mutations is a multisystem disease with vascular complications. Following a myocardial infarction (MI) from a coronary artery aneurysm in a 43-year-old patient, our center began MRI screening for coronary vessel changes. This project aims to identify the prevalence of coronary artery dilation or tortuosity in STAT3-HIES and changes over time. Methods We reviewed coronary artery MRIs of patients with STAT3-HIES, identifying 134 patients with 345 studies from 2006 to 2025, representing 70% of our cohort. We typically repeat imaging every 3 years. Results Patients were 7–64 years (median 21) at baseline imaging and ranged from 7 to 74 years, including all studies. Seventy-six of the patients were female (57%), 122 living. At baseline imaging, 56 patients (42%) had normal-appearing coronary arteries. Tortuosity of the right coronary artery (RCA) was seen in 56 patients (42 %), and dilation of the left anterior descending coronary artery (LAD) was seen in 19 patients (14%). Eighty-eight patients had repeat imaging over 1–18 years (median 10), average 3.4 MRIs. 37 patients (42%) had imaging that worsened over time with either increased dilation or tortuosity. Three patients had myocardial infarctions related to coronary artery dilation/aneurysm; all were started on antiplatelet agents, and recurrence was seen in one patient. Hypertension occurs in about one-third of patients with STAT3-HIES. In the patients with multiple images, 5 (19%) had hypertension with normal coronary arteries over time, compared to 11 (52%) with abnormal coronary arteries but no changes over time, and 16 (44%) with worsening changes. Six patients underwent hematopoietic stem cell transplant at ages 7–20 years (median 16); three of the five with post-transplant imaging had new RCA tortuosity. Conclusions Complications from middle-sized arterial abnormalities in STAT3-HIES include subarachnoid hemorrhage from cerebral aneurysm and myocardial infarction from clot in coronary artery aneurysms. Tortuosity and dilation of the coronary arteries are common in STAT3-HIES. Patients should be screened to allow for antiplatelet therapy if a coronary artery aneurysm is present. Further study is needed regarding the role of hypertension affecting coronary artery changes and whether hematopoietic stem cell transplantation (HSCT) provides additional vascular risk.
2026-03-05 | JAK-STAT signaling: molecular mechanism and targeted treatment in dento-maxillofacial abnormalities.
Dento-maxillofacial abnormalities are highly prevalent and arise as a result of a variety of etiological factors, presenting substantial challenges to treatment. The JAK-STAT signaling plays a pivotal role in dentofacial development, regulating endochondral ossification, intramembranous ossification, dental follicle formation, and enamel development. Mutations in the JAK-STAT signaling lead to syndromes associated with severe dento-maxillofacial abnormalities, including Growth Hormone Insensitivity Syndrome and Autosomal Dominant Hyper-IgE Syndrome. Corresponding mouse disease models have been developed to simulate the phenotypes observed in clinical patients and investigate their underlying mechanism. Meanwhile, several medications targeting JAK-STAT signaling, including baricitinib and imatinib, have been developed for clinical application, demonstrating significant effects in skeletal disorders such as osteoporosis and osteoarthritis, indicating promising effects in development and abnormalities of dento-maxillofacial. In this review, we aim to summarize the role of JAK-STAT signaling in the development and abnormalities of dento-maxillofacial bone, and the relevant molecules that may be utilized for clinical treatment, to shed new light on the precise treatment of dento-maxillofacial abnormalities.
cell therapies
2026-08-13 | Hyper-IgE syndromes in pediatrics: clinical spectrum, differential diagnosis, and management
Abstract Hyper-IgE syndromes (HIES) are rare inborn errors of immunity (≈1 per million) caused by pathogenic variants in STAT3, DOCK8 or IL6ST. They present with very high serum immunoglobulin E (IgE), recurrent bacterial or fungal infections, eczema and characteristic organ involvement. The autosomal dominant STAT3-deficient form features early-onset eczema, “cold” abscesses, recurrent pneumonias with pneumatoceles and skeletal or dental anomalies. Autosomal recessive forms such as DOCK8 or PGM3 deficiency show a more severe phenotype with viral skin infections, allergy, asthma and increased malignancy risk. HIES should be suspected in children with IgE >2000 IU/mL plus recurrent sinopulmonary or skin infections, severe eczema, atypical viral infections or a National Institutes of Health Hyper-IgE Syndrome (NIH HIES) score >40. Differentiation from severe atopic dermatitis, asthma, eosinophilic disorders and parasitic infections is essential. Evaluation includes eosinophils, lymphocyte subsets, T-helper 17 (Th17) cell analysis and targeted genetic testing. Management involves antimicrobial prophylaxis, treatment of complications, dermatologic care and genotype-based hematopoietic stem cell transplantation (HSCT), which is curative in DOCK8 but less effective in STAT3 deficiency. Early genomic confirmation enables timely recognition, identification of red flags, and genotype-specific therapy to improve long-term outcomes.
2026-06-02 | [Allogeneic Hematopoietic Stem Cell Transplantation for Children with Hyper-IgE Syndrome].
To summarize the clinical characteristics, treatment outcomes, and prognosis of two children with STAT3 gene mutation-associated hyper-IgE syndrome(HIES) who underwent allogeneic hematopoietic stem cell transplantation(allo-HSCT). A retrospective analysis was performed on two pediatric patients with STAT3-mutated HIES (STAT3-HIES) who received allo-HSCT. Data included baseline clinical features, transplant protocols, post-transplant outcomes, complications (graft-versus-host disease, infection, virus reactivation), serum IgE levels, and long-term follow-up. The two patients (one male, one female; ages 2 years 10 months and 10 years 10 months at transplant) received peripheral blood stem cells from HLA 9/10-matched unrelated donors and were conditioned with the classic BUCY regimen(busulfan+cyclophosphamide+antithymocyte globulin). Neutrophils and platelets engraftment were achieved on day+11 and day +9/+11, respectively. Complete donor chimerism(100%) was confirmed on day+15 post-transplant. No grade II-IV acute GVHD or viral reactivation occurred. Serum IgE levels decreased markedly at 30 days post-transplant compared to pre-transplant. Pulmonary CT findings (e.g., infection foci,cavitation) improved significantly. By the last follow-up (April 30, 2025), both children survived, and their quality of life improved significantly (infection control, resolution of skin eczema, and improvementin organ function). For children with STAT3-mutated HIES who experience recurrent severe respiratory infections impairing quality of life, allo-HSCT with a suitable donor can effectively control infection, improve immune abnormalities, and long-term outcomes.
2025-06-21 | Allogeneic hematopoietic stem cell transplantation for STAT3 hyper-IgE syndrome: a worldwide study.
Signal transduction and activator of transcription 3 hyperimmunoglobulin E syndrome (STAT3-HIES) is a multisystem disorder causing recurrent skin and respiratory infection with bronchiectasis, pneumatoceles, and aspergillosis; lymphoma; and extraimmune manifestations including fractures and vasculopathy. Published data on immune and extraimmune hematopoietic stem cell transplant (HSCT) outcomes focus on case reports or small cohorts. We conducted an international multicenter retrospective study of HSCT in STAT3-HIES. Primary end points were overall survival (OS) and event-free survival (EFS; events were death, graft failure, chronic graft-versus-host disease [GVHD]). We identified 41 patients over a 28-year period. HSCT indication was infection (93%) or lymphoma (7%). Median age at HSCT was 14 years (range, 4-45). Most patients had pre-HSCT respiratory disease (93%), including parenchymal lung disease (68%), and prior suspected/confirmed pulmonary fungal infection (32%). Patients received peripheral blood stem cells (51%) or marrow (49%) from HLA 10/10-matched unrelated donors (44%), matched family donors (44%), mismatched family donors (10%), or 1 9/10-mismatched unrelated donor (2%). Conditioning regimens were predominantly treosulfan-based (59%; with thiotepa, 34%); other patients received busulfan-based (24%) or melphalan-based (17%) regimens. Median follow-up for surviving patients was 5 years (0.8-28). The 5-year OS was 93%, and 5-year EFS 90%. Cumulative incidence of grade 2 to 4 acute GVHD was 22%. Median whole blood donor chimerism at latest follow-up was 100%. Eighty-seven percent of patients have reduced or no bacterial or fungal respiratory infection. After HSCT, 20% developed new skeletal fractures. This worldwide study expanded data on HSCT for STAT3-HIES to 41 patients; despite significant pre-HSCT pulmonary morbidity, OS was high, and patients have improved skin and respiratory disease though the impact on extraimmune manifestations appears limited.
2025-05-13 | Haploidentical stem cell transplantation in DOCK8 deficiency: a case report of successful outcomes.
DOCK8 deficiency syndrome, formerly known as autosomal recessive hyper-IgE syndrome (AR-HIES), is a rare combined immunodeficiency disorder characterized by recurrent infections, eczema, eosinophilia, and elevated immunoglobulin E (IgE) levels. We present a case of a 6-year-old girl with DOCK8 deficiency syndrome, who experienced recurrent skin infections and molluscum contagiosum since infancy. Genetic testing confirmed the diagnosis. Due to the high morbidity and mortality associated with DOCK8 deficiency syndrome, she underwent hematopoietic stem cell transplantation (HSCT) from her father. Posttransplant, the patient's skin condition significantly improved, and she achieved full donor chimerism. This case highlights the importance of considering DOCK8 deficiency in patients with recurrent infections, eczema, eosinophilia, and high IgE levels, and the potential curative effect of HSCT for these patients.
2024-10-26 | Pathophysiology of Congenital High Production of IgE and Its Consequences: A Narrative Review Uncovering a Neglected Setting of Disorders.
Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.
antibodies
2026-07-15 | A Rare Case of Hyper-IgE Syndrome in a Two-Year-Old Child with Recurrent Pneumonia and Generalized Eczematous Dermatitis
Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare primary immunodeficiency disorder characterized by markedly elevated serum immunoglobulin E (IgE) levels, recurrent sinopulmonary and cutaneous infections, chronic eczematous dermatitis, eosinophilia, and skeletal or connective tissue abnormalities. The autosomal dominant form is most commonly caused by mutations in the STAT3 gene, resulting in impaired T-helper 17 (Th17) cell differentiation and defective neutrophil recruitment. The rarity of the disorder, overlapping clinical manifestations with atopic dermatitis and bronchial asthma, and variable disease severity frequently delay diagnosis, thereby increasing the risk of irreversible pulmonary complications such as bronchiectasis and pneumatoceles. Early recognition and multidisciplinary management are therefore essential to reduce morbidity and improve long-term outcomes.
2026-05-29 | How I Treat: STAT3 hyper IgE syndrome
STAT3 hyper IgE syndrome (STAT3-HIES) is a rare inborn error of immunity characterized by chronic eczema, recurrent bacterial and fungal infections, markedly elevated serum IgE levels, and a broad spectrum of skeletal, dental, vascular, and gastrointestinal manifestations. Despite increasing insight into the genetic and immunologic basis of STAT3-HIES, detailed, treatment-oriented guidance for clinical practice remains limited. This article provides a pragmatic management guideline for STAT3-HIES. Clinical and laboratory criteria that should prompt suspicion and select patients for genetic testing are discussed. The therapeutic sections cover acute and prophylactic antibacterial treatment, antimicrobial eradication strategies, antifungal therapy, and immunoglobulin replacement therapy. The treatment of severe eczema, organ-specific care for lung, skeletal, vascular, and dental involvement, vaccinations, and supportive measures including physiotherapy and psychosocial support, as well as approaches to pregnancy management, family planning, and genetic counseling are outlined. Furthermore, hematopoietic stem cell transplantation is discussed. This management-focused approach complements existing reviews and aims to standardize care for patients with STAT3-HIES across centers and disciplines.
2026-05-01 | A Novel IL6ST Variant in an Adolescent with Recurrent Abscesses and Eczema Treated with Dupilumab
We present the case of a 17-year-old male with a long-standing history of recurrent and persistent cutaneous abscesses beginning at 6 years of age. Lesions were widespread, affecting the scalp, trunk, buttocks, and extremities, and characterized by painful, indurated nodules that drained purulent fluid spontaneously and resolved over 5–10 days, often with pruritus and residual scarring. He denied fevers or other systemic symptoms. Multiple antibiotic courses provided no sustained improvement. A punch biopsy at age 14 years demonstrated a suppurative granulomatous infiltrate. Bacterial cultures grew Staphylococcus aureus on two occasions, while fungal and Acid-Fast Bacillus (AFB) cultures remained negative. Partial clinical improvement on rifampin and azithromycin raised suspicion for an atypical acid-fast bacillary infection and potential underlying immunodeficiency; however, repeat cultures for nontuberculous mycobacteria were persistently negative, and the diagnosis was not confirmed. Past medical history was also notable only for several otitis media episodes as a child. There was no history of pneumonia, fractures, dysmorphic features, delayed dentition, joint hypermobility, candida infections, or childhood eczema. Family history included severe acne and recurrent boils in the father, atopic disease in the mother, and two healthy siblings. Immunologic evaluation revealed normal lymphocyte subsets, intact mitogen and antigen proliferation responses, normal neutrophil oxidative burst, and normal quantitative immunoglobulins. He had adequate vaccine responses to protein and polysaccharide antigens. IgE was markedly elevated at 6,757 IU/mL with mild eosinophilia. A comprehensive primary immunodeficiency genetic panel identified a variant of uncertain significance in IL6ST at c.1405G>C (p.Asp469His), a gene associated with autosomal-dominant and autosomal recessive Hyper-IgE syndrome. This missense variant is absent from population databases and has not been previously reported in individuals with IL6ST-related disease. It is population frequency on gnomAD (v4.1.0) is 0.0000006199, Combined Annotation Dependent Depletion (CADD) score of 25.9, and a PolyPhen score of 0.940 (which categorizes it as probably damaging). He subsequently developed atopic dermatitis involving the scalp and flexural regions of his extremities. Although never used in patients with IL6ST, dupilumab was initiated in light of emerging evidence that it can lead to marked improvement in cutaneous and systemic symptoms in select Hyper-IgE phenotypes. His clinical response is being closely monitored.
2026-05-01 | Clinical features, genetics, treatment, and long-term outcomes of STAT3 hyper-IgE syndrome: Single-center cohort analysis.
Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic manifestations. We sought to characterize the spectrum of clinical manifestations, genetics, treatment approaches, and long-term outcomes of patients with STAT3-HIES. Clinical features, laboratory findings, treatment, and survival were reviewed in the largest single-center STAT3-HIES cohort (n = 164) prospectively followed under a natural history protocol (NCT00006150). In addition to the classic skin, lung, dental, and musculoskeletal manifestations captured in the 1999 scoring system, we comprehensively characterized disease phenotypes across multiple organ systems, including previously underrecognized features. Lung disease remained the major morbidity with both infectious and parenchymal complications. During longitudinal follow-up, age-related vascular and skeletal degeneration emerged and significantly affected quality of life in patients 45 years and older. No genotype-phenotype correlations were identified. In terms of management, optimal supportive measures, including antimicrobials and immunoglobulin replacement therapy, tailored to disease features and individual risk factors, remained the primary approach. Dupilumab was used primarily for the eczematous dermatitis and demonstrated significant clinical benefit. In highly selected cases (n = 6), allogeneic hematopoietic stem cell transplantation was performed and showed reduction in infection burden. The median overall survival was 55 years-significantly shorter than that of the general United States population-and was not affected by sex, variant location, or proband status. STAT3-HIES is a multisystem disorder that requires multidisciplinary care. Early diagnosis and supportive measures have altered its natural history. Recognition and improved understanding of the nonimmunologic manifestations of this disorder will further improve patient outcomes.
2026-04-14 | Severe neonatal scalp abscesses as the initial presentation of STAT3-associated hyper IgE syndrome
Hyperimmunoglobulin E Syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent staphylococcal skin abscesses, chronic eczema, recurrent pulmonary infections, marked eosinophilia, and markedly elevated serum IgE levels. We describe a 2-month-old male infant who presented with diffuse, recurrent scalp abscesses progressing from the newborn period, accompanied by fever, periorbital swelling, persistent eosinophilia, and profound hyper-IgEemia. Failure of conventional therapy, recurrence of pustular lesions, and an IgE level of 3220 IU/mL raised strong suspicion for HIES. Genetic evaluation confirmed a heterozygous pathogenic STAT3 variant, establishing a diagnosis of autosomal dominant STAT3-HIES. This case highlights that early and isolated cutaneous infections in neonates may be the sentinel presentation of underlying immunodeficiency.
other
2025-09-01 | STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome.
The autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency, which originates from heterozygous missense mutations in the signal transducer and activator of transcription 3 (STAT3) gene. It is accepted that most STAT3 variants causing AD-HIES are dominant negative. Whether haploinsufficient mutations cause a phenotype in humans is still debated. We report on a family with a heterozygous STAT3 nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a Stat3 haploinsufficient (Stat3+/-) mouse model in which we found that Stat3+/- mice had increased IgE serum levels, reduced TH17 cell differentiation, and were susceptible to a cutaneous Staphylococcus aureus infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in STAT3 with residual protein expression as an important cause for immune deficiency. The implications extend to the diagnosis of immunodeficiency disorders and to the design of gene therapy in situations where gene dosage matters.
2023-09-21 | Allele-Specific Disruption of a Common STAT3 Autosomal Dominant Allele Is Not Sufficient to Restore Downstream Signaling in Patient-Derived T Cells.
Dominant negative mutations in the STAT3 gene account for autosomal dominant hyper-IgE syndrome (AD-HIES). Patients typically present high IgE serum levels, recurrent infections, and soft tissue abnormalities. While current therapies focus on alleviating the symptoms, hematopoietic stem cell transplantation (HSCT) has recently been proposed as a strategy to treat the immunological defect and stabilize the disease, especially in cases with severe lung infections. However, because of the potentially severe side effects associated with allogeneic HSCT, this has been considered only for a few patients. Autologous HSCT represents a safer alternative but it requires the removal of the dominant negative mutation in the patients' cells prior to transplantation. Here, we developed allele-specific CRISPR-Cas9 nucleases to selectively disrupt five of the most common STAT3 dominant negative alleles. When tested ex vivo in patient-derived hematopoietic cells, allele-specific disruption frequencies varied in an allele-dependent fashion and reached up to 62% of alleles harboring the V637M mutation without detectable alterations in the healthy STAT3 allele. However, assessment of the gene expression profiles of the STAT3 downstream target genes revealed that, upon activation of those edited patient cells, mono-allelic STAT3 expression (functional haploinsufficiency) is not able to sufficiently restore STAT3-dependent signaling in edited T cells cultured in vitro. Moreover, the stochastic mutagenesis induced by the repair of the nuclease-induced DNA break could further contribute to dominant negative effects. In summary, our results advocate for precise genome editing strategies rather than allele-specific gene disruption to correct the underlying mutations in AD-HIES.
2021-11-30 | Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing.
STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency presenting with destructive lung disease along with other symptoms. CRISPR-Cas9-mediated adenine base editors (ABEs) have the potential to correct one of the most common STAT3-HIES causing heterozygous STAT3 mutations (c.1144C>T/p.R382W). As a proof-of-concept, we successfully applied ABEs to correct STAT3 p.R382W in patient fibroblasts and induced pluripotent stem cells (iPSCs). Treated primary STAT3-HIES patient fibroblasts showed a correction efficiency of 29% ± 7% without detectable off-target effects evaluated through whole-genome and high-throughput sequencing. Compared with untreated patient fibroblasts, corrected single-cell clones showed functional rescue of STAT3 signaling with significantly increased STAT3 DNA-binding activity and target gene expression of CCL2 and SOCS3. Patient-derived iPSCs were corrected with an efficiency of 30% ± 6% and differentiated to alveolar organoids showing preserved plasticity in treated cells. In conclusion, our results are supportive for ABE-based gene correction as a potential causative treatment of STAT3-HIES.
2008-03-06 | Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency.
The purpose of the review is to provide recent insight into the pathogenesis and pathophysiology of hyperimmunoglobulin E syndrome. We recently identified a homozygous four base-pair deletion in the coding region of the tyrosine kinase 2 gene in a hyperimmunoglobulin E syndrome patient who exhibited susceptibility to intracellular bacteria. Hyperimmunoglobulin E syndrome is a primary immunodeficiency characterized by recurrent staphylococcal skin abscesses and pneumonia, and elevated serum immunoglobulin E. This syndrome is subdivided into types 1 and 2. Type 1 displays abnormalities in multiple systems, including the skeletal/dental and immune systems, whereas type 2 abnormalities are confined to the immune system. We recently identified a homozygous mutation in the tyrosine kinase 2 gene in a type 2 patient. Analyses of cytokine responses in the patient's cells revealed that the tyrosine kinase 2 deficiency had resulted in severe impairment of the signal transduction for multiple cytokines, including interleukin-6, -10, -12 and -23, and interferon-alpha/beta. The cytokine signals were successfully restored by transducing the intact tyrosine kinase 2 gene. Thus, tyrosine kinase 2 plays obligatory roles in human immunity. Based on this finding, we propose that hyperimmunoglobulin E syndrome is a primary immunodeficiency caused by genetic alterations leading to the defect in multiple cytokine signals.
2006-11-01 | Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity
Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
proteins
2026-04-13 | Dock8 regulates Th2 cell differentiation through ANXA1.
Dedicator of Cytokinesis 8 (DOCK8), a member of the DOCK family of guanine nucleotide exchange factors, serves as a key factor in managing the Rho GTPases activity, notably Cdc42 and Rac1, which control key cellular processes, including migration, adhesion, and phagocytosis. Mutations in the DOCK8 gene cause autosomal recessive hyper-IgE syndrome (AR-HIES), a primary immunodeficiency disorder characterized by elevated serum IgE levels, eczema, recurrent infections, and defective immune responses. In this study, a CRISPR/Cas9-generated Dock81281&1282 TG deletion mutation mouse model was constructed to investigate the immunological consequences of Dock8 deficiency. Our results demonstrate that Dock8 is essential for the peripheral homeostasis of T cells, particularly T follicular helper (Tfh), Th2, and regulatory T cells (Treg). Notably, in Dock8 mutant mice, both Th2 and Tfh cells were elevated, and they collaboratively promote IgE production. Additionally, we identified that Annexin A1 (ANXA1) enhances Th2 cell differentiation in Dock8 mutants, suggesting its potential role in restoring immune balance. These findings provide a refined understanding of the molecular mechanisms associated with DOCK8-related immune deficiencies and highlight potential therapeutic strategies for managing AR-HIES.
2025-12-09 | Successful Interferon-α Therapy for a Huge Lesion Including Eye and Eyelids
Introduction Defective T cell responses lead to insufficient interferon production, thereby compromising antiviral immunity and increasing vulnerability to viral infections in combined immunodeficiency disorders. The DOCK8 deficiency, also known as autosomal recessive (AR) hyper IgE syndrome (HIES), is a combined immunodeficiency characterized by susceptibility to eczema, respiratory tract infections, allergies, malignancies, autoimmunity, and cutaneous viral infections caused by herpes simplex virus, pox virus, human papillomavirus, molluscum contagiosum virus, and orf virus, along with elevated serum IgE levels and hypereosinophilia (Goker E et al., Pediatr Allergy Immunol 2022; 33: e13666). DOCK8 encodes a guanine nucleotide exchange factor that regulates the actin cytoskeletonʼs response to mitogenic and chemokine signals via the reversible activation of small G proteins, including cell division cycle 42 (Harada Y et al., Blood 2012; 119: 4451–4461). DOCK8 deficiency affects the migration, function, and viability of both innate and adaptive immune cells. The memory compartments of T and B cells, lymphoproliferation in response to mitogens, T cell migration, and NK cell cytotoxicity are predominantly diminished (Zhang Q et al., N Engl J Med 2009; 361: 2046–2055). Patients with DOCK8 deficiency suffer persistent cutaneous viral infections, potentially due to compromised actin cytoskeleton responses, which are crucial for immune cell migration to infection sites, and a reduction in plasmacytoid dendritic cells (pDC) that secrete essential type 1 interferons for viral clearance (Mizesko M et al., J Allergy Clin Immunol 2013; 131: 840–848). Type I interferons (IFNs) upregulate the expression of major histocompatibility complex molecules I and II, enhancing the presentation of viral peptides to cytotoxic T cells through conventional DCs, as well advocating NK functions. Both non-pegylated and pegylated IFN-α (PEG IFN-a) were used successful for difficult-to-treat cutaneous viral infections in a few patients with HIES (Al-Zahrani D et al., Clin Immunol 2014; 153: 104–108; Papan C et al., J Allergy Clin Immunol 2014; 133: 1456–1458; Kilic S et al., Pediatrics 2006; 117: e1253–e1255; Benninghoff U et al., Pediatr Allergy Immunol 2008; 19: 564–568). Publication History Received: 22 May 2025 Accepted after revision: 05 November 2025 Article published online: 09 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-12-08 | Environmental exposures, epithelial barrier dysfunction, and the evolving landscape of allergic disorders and asthma.
Immediate hypersensitivity disorders, such as asthma, food intolerance, and anaphylaxis, have risen dramatically since the 20th century, marking a shift in the global disease burden. While mast cells have been associated with IgE-mediated disorders, they also play important roles in homeostasis. To prevent chronic inflammation and aberrant tissue remodeling, tight regulation of mast cells is essential in response to microorganisms, autoantigens, and environmental changes. The surge in mast cell-mediated disorders and evidence of mast cell interactions with epithelial and neural networks have led to the epithelial barrier hypothesis. This hypothesis extends the protective role of the epithelium by highlighting its integrated communication with both the nervous and immune systems, proposing that dysregulated nerve-mast cell signaling at epithelial barriers contributes to the development of immediate hypersensitivity disorders - both allergic and nonallergic phenotypes. In turn, it offers new strategies for prevention and treatment, focusing on restoring barrier integrity and modulating neuroimmune pathways. Clinical populations including hypermobility syndromes, such as certain Ehlers-Danlos syndrome variants and Job syndrome, exemplify the systemic consequences of disrupted epithelial barriers and chronic nerve-mast cell dysregulation. Accordingly, this review discusses the co-emergence of hypersensitivity and hypermobility syndromes as manifestations of immune-neuro-epithelial dysfunction in the context of modern environmental change.
2024-07-21 | Allergic fungal rhinosinusitis linked to other hyper-IgE syndromes through defective TH17 responses.
In a gene expression analysis comparing sinus mucosa samples from allergic fungal rhinosinusitis (AFRS) patients with samples from non-AFRS chronic rhinosinusitis with nasal polyp (CRSwNP) patients, the antimicrobial peptide (AMP) histatin 1 (HTN1) was found to be the most differentially downregulated gene in AFRS. We sought to identify the molecular etiology of the downregulated expression of HTN1. We used RT-PCR to compare the expression of AMPs and a fungistasis assay to evaluate the antifungal activity of sinus secretions. Using flow cytometry, we characterized the presence of TH17/TH22 cells and signal transducer and activator of transcription (STAT) signaling from AFRS patients, non-AFRS CRSwNP patients, and healthy controls. We confirmed decreased expression of AMPs in AFRS sinus mucosa with concordant decrease in antifungal activity in sinus secretions. IL-22 and IL-22-producing T cells were deficient within sinus mucosa of AFRS patients. In vitro studies demonstrated a defect in IL-6/STAT3 signaling critical for TH17/TH22 differentiation. Epithelial cells from AFRS patients could express AMPs when stimulated with exogenous IL-22/IL-17 and circulating TH17 cell abundance was normal. Similar to other hyper-IgE syndromes, but distinct from CRSwNP, AFRS patients express a defect in STAT3 activation limited to IL-6-dependent STAT3 phosphorylation that is critical for TH17/TH22 differentiation. This defect leads to a local deficiency of IL-17/IL-22 cytokines and deficient AMP expression within diseased sinus mucosa of AFRS patients. Our findings support evaluation of therapeutic approaches that enhance airway AMP production in AFRS.
2024-06-17 | Extracellular Vesicles based STAT3 delivery as innovative therapeutic approach to restore STAT3 signaling deficiency.
Extracellular Vesicles (EVs) have been proposed as a promising tool for drug delivery because of their natural ability to cross biological barriers, protect their cargo, and target specific cells. Moreover, EVs are not recognized by the immune system as foreign, reducing the risk of an immune response and enhancing biocompatibility. Herein, we proposed an alternative therapeutic strategy to restore STAT3 signaling exploiting STAT3 loaded EVs. This approach could be useful in the treatment of Autosomal Dominant Hyper-IgE Syndrome (AD-HIES), a rare primary immunodeficiency and multisystem disorder due to the presence of mutations in STAT3 gene. These mutations alter the signal transduction of STAT3, thereby impeding Th17 CD4+ cell differentiation that leads to the failure of immune response. We set up a simple and versatile method in which EVs were loaded with fully functional STAT3 protein. Moreover, our method allows to follow the uptake of STAT3 loaded vesicles inside cells due to the presence of EGFP in the EGFP-STAT3 fusion protein construct. Taken together, the data presented in this study could provide the scientific background for the development of new therapeutic strategy aimed to restore STAT3 signaling in STAT3 misfunction associated diseases like AD-HIES. In the future, the administration of fully functional wild type STAT3 to CD4+ T cells of AD-HIES patients might compensate its loss of function and would be beneficial for these patients, lowering the risk of infections, the use of medications, and hospitalizations.
small molecules
2026-07-20 | The V3 Phase Architecture Applied to the Entire Human Humoral Immune System: A Complete, Certifiable Ada/SPARK Framework Simulating the Assembly of All Four Immunoglobulin Isotypes (IgM, IgG, IgA, IgE) with Pathological Stress Testing Across 10 Immunological Diseases — Validated by Inverse Invariant Collapse and GNATprove 100%
s ABSTRACT: Background & Biological Hypothesis: Classical immunology often views humoral immunodeficiencies, autoimmune disorders, and hypersensitivity reactions as isolated biochemical anomalies governed by complex molecular cascades. This study provides formal proof for a novel biophysical paradigm: human humoral immunity functions as a unified phase-equilibrium system governed by deterministic biophysical invariants (V3 energy invariant Ψ_V3 = 48,016.8 kg/m² and critical bioelectric potential Φ_critical = -51.1 mV). Within this framework, biological health is defined as structural phase stability, whereas immune pathologies represent predictable, threshold-driven phase ruptures. Biological Proof & Mechanistic Discovery: Through high-integrity computational modeling of all four major immunoglobulin classes (IgM, IgG, IgA, IgE), we demonstrate that specific immunopathologies do not occur randomly, but are triggered precisely when individual biophysical parameters cross non-negotiable physical thresholds: • IgM & Assembly Topology: Pentameric IgM integrity requires strict k = 7 heptadic closure via the J-chain. We prove that a drop below k = 5 prevents ring closure, dumping truncated monomers into the bloodstream and causing Waldenström macroglobulinemia. Furthermore, an bioelectric potential shift above Φ > -40.0 mV disrupts polypeptide folding energy, triggering Selective IgM Deficiency, while loss of vesicular transport coherence (< 50%) leads to Hyper-IgM Syndrome. • IgG & Structural Flexibility: Proper H2L2 domain folding coherence is required for secretable IgG; falling below 60% coherence triggers endo-reticular degradation, causing Hypogammaglobulinemia. Hinge region destabilization below 70% impairs receptor binding dynamics, causing Myasthenia Gravis, while endosomal pH-FcRn gradient disruption halts maternal-fetal transfer, driving Hemolytic Disease of the Fetus and Newborn (HDFN). • IgA & Mucosal Shielding: Mucosal protection strictly depends on the presence of the Secretory Component (SC); its absence completely strips mucosal immunity, resulting in Selective IgA Deficiency. Additionally, hinge O-glycosylation below an 80% threshold alters protein solubility, proving that IgA Nephropathy (Berger’s Disease) is driven by threshold-dependent glomerular self-aggregation. • IgE & Allergic Signaling: IgE over-coherence (> 90%) drives unchecked production seen in Hyper-IgE (Job's) Syndrome. Conversely, when allergen-mediated FcεRI crosslinking density exceeds 30%, the mast-cell membrane equilibrium collapses instantly, releasing massive histamine surges in Anaphylactic Shock. Significance for Immunology: This work formally proves that immunological diseases are quantifiable physical phase ruptures. By mapping ten distinct clinical conditions to exact mathematical thresholds, the V3 framework demonstrates that humoral pathologies share a single universal law of phase rupture. This transforms clinical immunology from a descriptive science into a predictive, deterministic biophysical discipline, offering a new foundation for therapeutic target design and precision immunotherapeutics.
2026-06-17 | [Guillain-Barré syndrome following allogeneic hematopoietic stem cell transplantation in a pediatric patient: a case report and literature review].
A 10-year-old girl diagnosed with hyper-IgE syndrome for more than six years developed dizziness and symmetrical progressive limb weakness one week prior to hospital admission, occurring 4 months after allogeneic hematopoietic stem cell transplantation. On post-transplant day 121, dizziness and progressive, symmetric limb weakness appeared. Cerebrospinal fluid analysis revealed albuminocytologic dissociation. Electromyography confirmed multiple peripheral nerve lesions, consistent with the diagnosis of Guillain-Barré syndrome. Intravenous immunoglobulin therapy showed limited efficacy, whereas corticosteroid therapy produced significant clinical improvement. Neurological symptoms fully resolved after treatment; however, severe chronic graft-versus-host disease occurred subsequently. Based on this case, related literature was reviewed and summarized to provide references for early diagnosis, mechanistic investigation, and treatment options.
2026-05-10 | Tofacitinib as a Successful Treatment for Hyper-IgE Syndrome and Autoimmunity Associated with Constitutive Activation of JAK3.
The Janus Kinase 3 (JAK3) germline gain-of-function (GOF) mutation is a rare inborn error of immunity, first reported in 2020, characterized by lymphopenia and chronic NK-cell proliferation. However, its role in autoimmunity remains unclear, and no direct association with hyper-IgE syndrome (HIES) has been established. In this study, we describe a patient presenting with HIES, myositis, lymphopenia, and autoimmune hypothyroidism. Whole-exome sequencing identified a novel compound heterozygous JAK3 mutation (c.2524_2525delinsTT and c.2805G > C), predicted to be deleterious. Flow cytometry and RNA sequencing of peripheral blood mononuclear cells revealed a significant reduction in T cells and NK cells, particularly naïve CD4+ T cells, accompanied by a marked imbalance in T cell subsets. This led to constitutive activation of JAK1 and JAK3, along with increased STAT3 and STAT5 phosphorylation. Tofacitinib treatment significantly improved the patient's symptoms. Our findings expand the clinical spectrum of JAK3-associated immune dysregulation, linking it for the first time to HIES and multiple autoimmune manifestations. Furthermore, this study suggests that tofacitinib may be a potential therapeutic option for JAK3 signaling-associated immune dysregulation.
2026-05-01 | Coronary Artery Dilation and Tortuosity in STAT3DN Hyper IgE Syndrome
Background Hyper IgE syndrome from dominant-negative STAT3 mutations is a multisystem disease with vascular complications. Following a myocardial infarction (MI) from a coronary artery aneurysm in a 43-year-old patient, our center began MRI screening for coronary vessel changes. This project aims to identify the prevalence of coronary artery dilation or tortuosity in STAT3-HIES and changes over time. Methods We reviewed coronary artery MRIs of patients with STAT3-HIES, identifying 134 patients with 345 studies from 2006 to 2025, representing 70% of our cohort. We typically repeat imaging every 3 years. Results Patients were 7–64 years (median 21) at baseline imaging and ranged from 7 to 74 years, including all studies. Seventy-six of the patients were female (57%), 122 living. At baseline imaging, 56 patients (42%) had normal-appearing coronary arteries. Tortuosity of the right coronary artery (RCA) was seen in 56 patients (42 %), and dilation of the left anterior descending coronary artery (LAD) was seen in 19 patients (14%). Eighty-eight patients had repeat imaging over 1–18 years (median 10), average 3.4 MRIs. 37 patients (42%) had imaging that worsened over time with either increased dilation or tortuosity. Three patients had myocardial infarctions related to coronary artery dilation/aneurysm; all were started on antiplatelet agents, and recurrence was seen in one patient. Hypertension occurs in about one-third of patients with STAT3-HIES. In the patients with multiple images, 5 (19%) had hypertension with normal coronary arteries over time, compared to 11 (52%) with abnormal coronary arteries but no changes over time, and 16 (44%) with worsening changes. Six patients underwent hematopoietic stem cell transplant at ages 7–20 years (median 16); three of the five with post-transplant imaging had new RCA tortuosity. Conclusions Complications from middle-sized arterial abnormalities in STAT3-HIES include subarachnoid hemorrhage from cerebral aneurysm and myocardial infarction from clot in coronary artery aneurysms. Tortuosity and dilation of the coronary arteries are common in STAT3-HIES. Patients should be screened to allow for antiplatelet therapy if a coronary artery aneurysm is present. Further study is needed regarding the role of hypertension affecting coronary artery changes and whether hematopoietic stem cell transplantation (HSCT) provides additional vascular risk.
2026-03-05 | JAK-STAT signaling: molecular mechanism and targeted treatment in dento-maxillofacial abnormalities.
Dento-maxillofacial abnormalities are highly prevalent and arise as a result of a variety of etiological factors, presenting substantial challenges to treatment. The JAK-STAT signaling plays a pivotal role in dentofacial development, regulating endochondral ossification, intramembranous ossification, dental follicle formation, and enamel development. Mutations in the JAK-STAT signaling lead to syndromes associated with severe dento-maxillofacial abnormalities, including Growth Hormone Insensitivity Syndrome and Autosomal Dominant Hyper-IgE Syndrome. Corresponding mouse disease models have been developed to simulate the phenotypes observed in clinical patients and investigate their underlying mechanism. Meanwhile, several medications targeting JAK-STAT signaling, including baricitinib and imatinib, have been developed for clinical application, demonstrating significant effects in skeletal disorders such as osteoporosis and osteoarthritis, indicating promising effects in development and abnormalities of dento-maxillofacial. In this review, we aim to summarize the role of JAK-STAT signaling in the development and abnormalities of dento-maxillofacial bone, and the relevant molecules that may be utilized for clinical treatment, to shed new light on the precise treatment of dento-maxillofacial abnormalities.
cell therapies
2026-08-13 | Hyper-IgE syndromes in pediatrics: clinical spectrum, differential diagnosis, and management
Abstract Hyper-IgE syndromes (HIES) are rare inborn errors of immunity (≈1 per million) caused by pathogenic variants in STAT3, DOCK8 or IL6ST. They present with very high serum immunoglobulin E (IgE), recurrent bacterial or fungal infections, eczema and characteristic organ involvement. The autosomal dominant STAT3-deficient form features early-onset eczema, “cold” abscesses, recurrent pneumonias with pneumatoceles and skeletal or dental anomalies. Autosomal recessive forms such as DOCK8 or PGM3 deficiency show a more severe phenotype with viral skin infections, allergy, asthma and increased malignancy risk. HIES should be suspected in children with IgE >2000 IU/mL plus recurrent sinopulmonary or skin infections, severe eczema, atypical viral infections or a National Institutes of Health Hyper-IgE Syndrome (NIH HIES) score >40. Differentiation from severe atopic dermatitis, asthma, eosinophilic disorders and parasitic infections is essential. Evaluation includes eosinophils, lymphocyte subsets, T-helper 17 (Th17) cell analysis and targeted genetic testing. Management involves antimicrobial prophylaxis, treatment of complications, dermatologic care and genotype-based hematopoietic stem cell transplantation (HSCT), which is curative in DOCK8 but less effective in STAT3 deficiency. Early genomic confirmation enables timely recognition, identification of red flags, and genotype-specific therapy to improve long-term outcomes.
2026-06-02 | [Allogeneic Hematopoietic Stem Cell Transplantation for Children with Hyper-IgE Syndrome].
To summarize the clinical characteristics, treatment outcomes, and prognosis of two children with STAT3 gene mutation-associated hyper-IgE syndrome(HIES) who underwent allogeneic hematopoietic stem cell transplantation(allo-HSCT). A retrospective analysis was performed on two pediatric patients with STAT3-mutated HIES (STAT3-HIES) who received allo-HSCT. Data included baseline clinical features, transplant protocols, post-transplant outcomes, complications (graft-versus-host disease, infection, virus reactivation), serum IgE levels, and long-term follow-up. The two patients (one male, one female; ages 2 years 10 months and 10 years 10 months at transplant) received peripheral blood stem cells from HLA 9/10-matched unrelated donors and were conditioned with the classic BUCY regimen(busulfan+cyclophosphamide+antithymocyte globulin). Neutrophils and platelets engraftment were achieved on day+11 and day +9/+11, respectively. Complete donor chimerism(100%) was confirmed on day+15 post-transplant. No grade II-IV acute GVHD or viral reactivation occurred. Serum IgE levels decreased markedly at 30 days post-transplant compared to pre-transplant. Pulmonary CT findings (e.g., infection foci,cavitation) improved significantly. By the last follow-up (April 30, 2025), both children survived, and their quality of life improved significantly (infection control, resolution of skin eczema, and improvementin organ function). For children with STAT3-mutated HIES who experience recurrent severe respiratory infections impairing quality of life, allo-HSCT with a suitable donor can effectively control infection, improve immune abnormalities, and long-term outcomes.
2025-06-21 | Allogeneic hematopoietic stem cell transplantation for STAT3 hyper-IgE syndrome: a worldwide study.
Signal transduction and activator of transcription 3 hyperimmunoglobulin E syndrome (STAT3-HIES) is a multisystem disorder causing recurrent skin and respiratory infection with bronchiectasis, pneumatoceles, and aspergillosis; lymphoma; and extraimmune manifestations including fractures and vasculopathy. Published data on immune and extraimmune hematopoietic stem cell transplant (HSCT) outcomes focus on case reports or small cohorts. We conducted an international multicenter retrospective study of HSCT in STAT3-HIES. Primary end points were overall survival (OS) and event-free survival (EFS; events were death, graft failure, chronic graft-versus-host disease [GVHD]). We identified 41 patients over a 28-year period. HSCT indication was infection (93%) or lymphoma (7%). Median age at HSCT was 14 years (range, 4-45). Most patients had pre-HSCT respiratory disease (93%), including parenchymal lung disease (68%), and prior suspected/confirmed pulmonary fungal infection (32%). Patients received peripheral blood stem cells (51%) or marrow (49%) from HLA 10/10-matched unrelated donors (44%), matched family donors (44%), mismatched family donors (10%), or 1 9/10-mismatched unrelated donor (2%). Conditioning regimens were predominantly treosulfan-based (59%; with thiotepa, 34%); other patients received busulfan-based (24%) or melphalan-based (17%) regimens. Median follow-up for surviving patients was 5 years (0.8-28). The 5-year OS was 93%, and 5-year EFS 90%. Cumulative incidence of grade 2 to 4 acute GVHD was 22%. Median whole blood donor chimerism at latest follow-up was 100%. Eighty-seven percent of patients have reduced or no bacterial or fungal respiratory infection. After HSCT, 20% developed new skeletal fractures. This worldwide study expanded data on HSCT for STAT3-HIES to 41 patients; despite significant pre-HSCT pulmonary morbidity, OS was high, and patients have improved skin and respiratory disease though the impact on extraimmune manifestations appears limited.
2025-05-13 | Haploidentical stem cell transplantation in DOCK8 deficiency: a case report of successful outcomes.
DOCK8 deficiency syndrome, formerly known as autosomal recessive hyper-IgE syndrome (AR-HIES), is a rare combined immunodeficiency disorder characterized by recurrent infections, eczema, eosinophilia, and elevated immunoglobulin E (IgE) levels. We present a case of a 6-year-old girl with DOCK8 deficiency syndrome, who experienced recurrent skin infections and molluscum contagiosum since infancy. Genetic testing confirmed the diagnosis. Due to the high morbidity and mortality associated with DOCK8 deficiency syndrome, she underwent hematopoietic stem cell transplantation (HSCT) from her father. Posttransplant, the patient's skin condition significantly improved, and she achieved full donor chimerism. This case highlights the importance of considering DOCK8 deficiency in patients with recurrent infections, eczema, eosinophilia, and high IgE levels, and the potential curative effect of HSCT for these patients.
2024-10-26 | Pathophysiology of Congenital High Production of IgE and Its Consequences: A Narrative Review Uncovering a Neglected Setting of Disorders.
Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.
antibodies
2026-07-15 | A Rare Case of Hyper-IgE Syndrome in a Two-Year-Old Child with Recurrent Pneumonia and Generalized Eczematous Dermatitis
Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare primary immunodeficiency disorder characterized by markedly elevated serum immunoglobulin E (IgE) levels, recurrent sinopulmonary and cutaneous infections, chronic eczematous dermatitis, eosinophilia, and skeletal or connective tissue abnormalities. The autosomal dominant form is most commonly caused by mutations in the STAT3 gene, resulting in impaired T-helper 17 (Th17) cell differentiation and defective neutrophil recruitment. The rarity of the disorder, overlapping clinical manifestations with atopic dermatitis and bronchial asthma, and variable disease severity frequently delay diagnosis, thereby increasing the risk of irreversible pulmonary complications such as bronchiectasis and pneumatoceles. Early recognition and multidisciplinary management are therefore essential to reduce morbidity and improve long-term outcomes.
2026-05-29 | How I Treat: STAT3 hyper IgE syndrome
STAT3 hyper IgE syndrome (STAT3-HIES) is a rare inborn error of immunity characterized by chronic eczema, recurrent bacterial and fungal infections, markedly elevated serum IgE levels, and a broad spectrum of skeletal, dental, vascular, and gastrointestinal manifestations. Despite increasing insight into the genetic and immunologic basis of STAT3-HIES, detailed, treatment-oriented guidance for clinical practice remains limited. This article provides a pragmatic management guideline for STAT3-HIES. Clinical and laboratory criteria that should prompt suspicion and select patients for genetic testing are discussed. The therapeutic sections cover acute and prophylactic antibacterial treatment, antimicrobial eradication strategies, antifungal therapy, and immunoglobulin replacement therapy. The treatment of severe eczema, organ-specific care for lung, skeletal, vascular, and dental involvement, vaccinations, and supportive measures including physiotherapy and psychosocial support, as well as approaches to pregnancy management, family planning, and genetic counseling are outlined. Furthermore, hematopoietic stem cell transplantation is discussed. This management-focused approach complements existing reviews and aims to standardize care for patients with STAT3-HIES across centers and disciplines.
2026-05-01 | A Novel IL6ST Variant in an Adolescent with Recurrent Abscesses and Eczema Treated with Dupilumab
We present the case of a 17-year-old male with a long-standing history of recurrent and persistent cutaneous abscesses beginning at 6 years of age. Lesions were widespread, affecting the scalp, trunk, buttocks, and extremities, and characterized by painful, indurated nodules that drained purulent fluid spontaneously and resolved over 5–10 days, often with pruritus and residual scarring. He denied fevers or other systemic symptoms. Multiple antibiotic courses provided no sustained improvement. A punch biopsy at age 14 years demonstrated a suppurative granulomatous infiltrate. Bacterial cultures grew Staphylococcus aureus on two occasions, while fungal and Acid-Fast Bacillus (AFB) cultures remained negative. Partial clinical improvement on rifampin and azithromycin raised suspicion for an atypical acid-fast bacillary infection and potential underlying immunodeficiency; however, repeat cultures for nontuberculous mycobacteria were persistently negative, and the diagnosis was not confirmed. Past medical history was also notable only for several otitis media episodes as a child. There was no history of pneumonia, fractures, dysmorphic features, delayed dentition, joint hypermobility, candida infections, or childhood eczema. Family history included severe acne and recurrent boils in the father, atopic disease in the mother, and two healthy siblings. Immunologic evaluation revealed normal lymphocyte subsets, intact mitogen and antigen proliferation responses, normal neutrophil oxidative burst, and normal quantitative immunoglobulins. He had adequate vaccine responses to protein and polysaccharide antigens. IgE was markedly elevated at 6,757 IU/mL with mild eosinophilia. A comprehensive primary immunodeficiency genetic panel identified a variant of uncertain significance in IL6ST at c.1405G>C (p.Asp469His), a gene associated with autosomal-dominant and autosomal recessive Hyper-IgE syndrome. This missense variant is absent from population databases and has not been previously reported in individuals with IL6ST-related disease. It is population frequency on gnomAD (v4.1.0) is 0.0000006199, Combined Annotation Dependent Depletion (CADD) score of 25.9, and a PolyPhen score of 0.940 (which categorizes it as probably damaging). He subsequently developed atopic dermatitis involving the scalp and flexural regions of his extremities. Although never used in patients with IL6ST, dupilumab was initiated in light of emerging evidence that it can lead to marked improvement in cutaneous and systemic symptoms in select Hyper-IgE phenotypes. His clinical response is being closely monitored.
2026-05-01 | Clinical features, genetics, treatment, and long-term outcomes of STAT3 hyper-IgE syndrome: Single-center cohort analysis.
Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder with both immunologic and nonimmunologic manifestations. We sought to characterize the spectrum of clinical manifestations, genetics, treatment approaches, and long-term outcomes of patients with STAT3-HIES. Clinical features, laboratory findings, treatment, and survival were reviewed in the largest single-center STAT3-HIES cohort (n = 164) prospectively followed under a natural history protocol (NCT00006150). In addition to the classic skin, lung, dental, and musculoskeletal manifestations captured in the 1999 scoring system, we comprehensively characterized disease phenotypes across multiple organ systems, including previously underrecognized features. Lung disease remained the major morbidity with both infectious and parenchymal complications. During longitudinal follow-up, age-related vascular and skeletal degeneration emerged and significantly affected quality of life in patients 45 years and older. No genotype-phenotype correlations were identified. In terms of management, optimal supportive measures, including antimicrobials and immunoglobulin replacement therapy, tailored to disease features and individual risk factors, remained the primary approach. Dupilumab was used primarily for the eczematous dermatitis and demonstrated significant clinical benefit. In highly selected cases (n = 6), allogeneic hematopoietic stem cell transplantation was performed and showed reduction in infection burden. The median overall survival was 55 years-significantly shorter than that of the general United States population-and was not affected by sex, variant location, or proband status. STAT3-HIES is a multisystem disorder that requires multidisciplinary care. Early diagnosis and supportive measures have altered its natural history. Recognition and improved understanding of the nonimmunologic manifestations of this disorder will further improve patient outcomes.
2026-04-14 | Severe neonatal scalp abscesses as the initial presentation of STAT3-associated hyper IgE syndrome
Hyperimmunoglobulin E Syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent staphylococcal skin abscesses, chronic eczema, recurrent pulmonary infections, marked eosinophilia, and markedly elevated serum IgE levels. We describe a 2-month-old male infant who presented with diffuse, recurrent scalp abscesses progressing from the newborn period, accompanied by fever, periorbital swelling, persistent eosinophilia, and profound hyper-IgEemia. Failure of conventional therapy, recurrence of pustular lesions, and an IgE level of 3220 IU/mL raised strong suspicion for HIES. Genetic evaluation confirmed a heterozygous pathogenic STAT3 variant, establishing a diagnosis of autosomal dominant STAT3-HIES. This case highlights that early and isolated cutaneous infections in neonates may be the sentinel presentation of underlying immunodeficiency.
other
2025-09-01 | STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome.
The autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency, which originates from heterozygous missense mutations in the signal transducer and activator of transcription 3 (STAT3) gene. It is accepted that most STAT3 variants causing AD-HIES are dominant negative. Whether haploinsufficient mutations cause a phenotype in humans is still debated. We report on a family with a heterozygous STAT3 nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a Stat3 haploinsufficient (Stat3+/-) mouse model in which we found that Stat3+/- mice had increased IgE serum levels, reduced TH17 cell differentiation, and were susceptible to a cutaneous Staphylococcus aureus infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in STAT3 with residual protein expression as an important cause for immune deficiency. The implications extend to the diagnosis of immunodeficiency disorders and to the design of gene therapy in situations where gene dosage matters.
2023-09-21 | Allele-Specific Disruption of a Common STAT3 Autosomal Dominant Allele Is Not Sufficient to Restore Downstream Signaling in Patient-Derived T Cells.
Dominant negative mutations in the STAT3 gene account for autosomal dominant hyper-IgE syndrome (AD-HIES). Patients typically present high IgE serum levels, recurrent infections, and soft tissue abnormalities. While current therapies focus on alleviating the symptoms, hematopoietic stem cell transplantation (HSCT) has recently been proposed as a strategy to treat the immunological defect and stabilize the disease, especially in cases with severe lung infections. However, because of the potentially severe side effects associated with allogeneic HSCT, this has been considered only for a few patients. Autologous HSCT represents a safer alternative but it requires the removal of the dominant negative mutation in the patients' cells prior to transplantation. Here, we developed allele-specific CRISPR-Cas9 nucleases to selectively disrupt five of the most common STAT3 dominant negative alleles. When tested ex vivo in patient-derived hematopoietic cells, allele-specific disruption frequencies varied in an allele-dependent fashion and reached up to 62% of alleles harboring the V637M mutation without detectable alterations in the healthy STAT3 allele. However, assessment of the gene expression profiles of the STAT3 downstream target genes revealed that, upon activation of those edited patient cells, mono-allelic STAT3 expression (functional haploinsufficiency) is not able to sufficiently restore STAT3-dependent signaling in edited T cells cultured in vitro. Moreover, the stochastic mutagenesis induced by the repair of the nuclease-induced DNA break could further contribute to dominant negative effects. In summary, our results advocate for precise genome editing strategies rather than allele-specific gene disruption to correct the underlying mutations in AD-HIES.
2021-11-30 | Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing.
STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency presenting with destructive lung disease along with other symptoms. CRISPR-Cas9-mediated adenine base editors (ABEs) have the potential to correct one of the most common STAT3-HIES causing heterozygous STAT3 mutations (c.1144C>T/p.R382W). As a proof-of-concept, we successfully applied ABEs to correct STAT3 p.R382W in patient fibroblasts and induced pluripotent stem cells (iPSCs). Treated primary STAT3-HIES patient fibroblasts showed a correction efficiency of 29% ± 7% without detectable off-target effects evaluated through whole-genome and high-throughput sequencing. Compared with untreated patient fibroblasts, corrected single-cell clones showed functional rescue of STAT3 signaling with significantly increased STAT3 DNA-binding activity and target gene expression of CCL2 and SOCS3. Patient-derived iPSCs were corrected with an efficiency of 30% ± 6% and differentiated to alveolar organoids showing preserved plasticity in treated cells. In conclusion, our results are supportive for ABE-based gene correction as a potential causative treatment of STAT3-HIES.
2008-03-06 | Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency.
The purpose of the review is to provide recent insight into the pathogenesis and pathophysiology of hyperimmunoglobulin E syndrome. We recently identified a homozygous four base-pair deletion in the coding region of the tyrosine kinase 2 gene in a hyperimmunoglobulin E syndrome patient who exhibited susceptibility to intracellular bacteria. Hyperimmunoglobulin E syndrome is a primary immunodeficiency characterized by recurrent staphylococcal skin abscesses and pneumonia, and elevated serum immunoglobulin E. This syndrome is subdivided into types 1 and 2. Type 1 displays abnormalities in multiple systems, including the skeletal/dental and immune systems, whereas type 2 abnormalities are confined to the immune system. We recently identified a homozygous mutation in the tyrosine kinase 2 gene in a type 2 patient. Analyses of cytokine responses in the patient's cells revealed that the tyrosine kinase 2 deficiency had resulted in severe impairment of the signal transduction for multiple cytokines, including interleukin-6, -10, -12 and -23, and interferon-alpha/beta. The cytokine signals were successfully restored by transducing the intact tyrosine kinase 2 gene. Thus, tyrosine kinase 2 plays obligatory roles in human immunity. Based on this finding, we propose that hyperimmunoglobulin E syndrome is a primary immunodeficiency caused by genetic alterations leading to the defect in multiple cytokine signals.
2006-11-01 | Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity
Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
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Drug Discovery Landscape
1 orphan drug designation for Hyper-IgE syndrome.
1 orphan drug designation for Hyper-IgE syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant humanized immunoglobulin gamma 1 monoclonal antibody (mAb) directed against the CemX segment of human membrane-bound immunoglobulin E (mIgE) | antibodies | FDA | 2017-09-28 | — | Oneness Biotech Co., Ltd. |
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