hyper-IgE Research Articles

Pulmonary manifestations in hyper IgE syndrome: A case series and review of Indian literature.

Recurrent pulmonary infections starting from childhood often prompt evaluation for primary immunodeficiency disorders (PIDs). Hyper IgE syndrome (HIES) is a less common PID characterised by recurrent skin and pulmonary infections associated with elevated IgE levels. Staphylococcal infections are more commonly seen in these individuals, resulting in structural lung abnormalities such as pneumatoceles and bronchiectasis. The associated non-immunologic features (characteristic facies, retained primary dentition, scoliosis, osteopenia, and hyperextensible joints) should raise suspicion of this syndrome. We present four cases of HIES and review the pulmonary manifestations in this disease as reported in the Indian literature.

DOCK8 deficiency due to a deep intronic variant in two kindreds with hyper-IgE syndrome

Dedicator of cytokinesis 8 (DOCK8) deficiency underlies the majority of cases of patients with autosomal recessive form of the hyper-immunoglobulin E syndrome (HIES). Most DOCK8 mutations involve deletions and splice junction mutations that abrogate protein expression. However, a few patients whose presentation is reminiscent of DOCK8 deficiency have no identifiable mutations. Using Whole Exome Sequencing (WES), we identified a deep intronic homozygous DOCK8 variant located in intron 36 (c.4626 + 76 A > G) in two unrelated patients with features of HIES that resulted in an in-frame 75 base pair intronic sequence insertion in DOCK8 cDNA, resulting in a premature stop codon (p.S1542ins6Ter). This variant resulted in variable decrease in DOCK8 expression that was associated with impaired T cell receptor-triggered actin polymerization, decreased IL-6-induced STAT3 phosphorylation, reduced expression of the Th17 cell markers CCR6 and IL-17, and higher frequencies of GATA3+ T cells indicative of Th2 skewing. Our approach extends the reach of WES in identifying disease-related intronic variants. It highlights the role of non-coding mutations in immunodeficiency disorders, including DOCK8 deficiency, and emphasizes the need to explore these mutations in unexplained inborn errors of immunity.

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.

Phenotypes of 126 Moroccan HIES patients according to NIH Score.

Hyper-IgE syndrome is a group of inborn errors of immunity, some of which are syndromic, characterized clinically by the classic triad of chronic eczema, cutaneous and/or pulmonary staphylococcal infections and high serum IgE concentrations (> 2000 IU/ml or > 10 x normal for age). We report here the clinical and immunological aspects of Moroccan patients presenting probable or possible HIES according to NIH-HIES score. This retrospective study covers the period from 1998 to 2023 and includes Moroccan patients with a clinical presentation suggestive of HIES (skin and/or pulmonary infections, eczema, high IgE levels) and an NIH score ≥ 20. We attempted to classify the patients phenotypically according to the 2022 IUIS IEI Expert Committee classification. Median age at symptom onset was 0.5 years and median age at diagnosis was 5.5 years. The main clinical signs were eczema (66%), skin abscesses (32.5%), pneumonia (32.5%), otitis (20%), mucocutaneous candidiasis (19%), diarrhea (12%), facial dysmorphism (10.3%), lymphadenopathy (9.5%), bronchial dilation (8%), pneumatoceles (8%), conjunctivitis (7.1%), rhinitis (6.3%), psychomotor delay (5.6%), pathological fractures (4%), retention of deciduous teeth (4%), cognitive delay (3.2%). This is the first clinical description of a cohort of Moroccan patients presenting HIES according to NIH criteria. Phenotype can sometimes orient towards identification of the mutated gene, but the overlapping clinical signs make molecular analysis necessary for genetic counseling and appropriate treatment.

A young female with endothelial dysfunction in a case of hyper IgE syndrome

Damage to corneal endothelium occurs during chronic inflammation due to the migration and deposition of mediators and cytokines involved in inflammatory cascade pathways. We report a case of a 22-year-old young female with hyper IgE syndrome with endothelial dysfunction. Endothelial dysfunction occurred due to the deposition of fibrin and induction of neutrophil chemotaxis. Hence, early diagnosis and treatment can reduce endothelial cell loss in chronic inflammatory processes.

Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome.

Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. The reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

Dysregulated Airway Host Defense in Hyper IgE Syndrome due to STAT3 Mutations.

Hyper IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES syndrome is characterized by chronic pulmonary infection and inflammation, suggesting impairment of pulmonary innate host defense. To identify airway epithelial host defense defects consequent to STAT3 mutations that, in addition to reported mutant STAT3 immunologic abnormalities, produce pulmonary infection. STAT3-HIES sputum was evaluated for biochemical/biophysical properties. STAT3-HIES excised lungs were harvested for histology; bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific mutation (R382W), expressed by lentiviruses, and a STAT3 knockout, generated by CRISPR/Cas9, were maintained in normal human bronchial epithelia under basal or inflammatory (IL1β) conditions. Effects of STAT3 deficiency on transcriptomics, and epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed. Mucus concentrations and viscoelasticity were increased in STAT3-HIES sputum. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 deficiency impaired CFTR-dependent fluid and mucin secretion, inhibited expression of antimicrobial peptides, cytokines, and chemokines, and acidified airway surface liquid at baseline and post-IL1β exposure in vitro. Notably, mutant STAT3 suppressed IL1R1 expression. STAT3 mutations also inhibited ciliogenesis in vivo and impaired mucociliary transport in vitro, a process mediated via HES6 suppression. Administration of a γ-secretase inhibitor increased HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells. STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with STAT3-HIES immune deficiency, contributes to chronic pulmonary infection.

Neutrophil-avid nanocarrier uptake by STAT3 dominant-negative hyper-IgE syndrome patient neutrophils.

Recurrent infections are a hallmark of STAT3 dominant-negative hyper-IgE syndrome (STAT3 HIES), a rare immunodeficiency syndrome previously known as Jobs syndrome, along with elevated IgE levels and impaired neutrophil function. We have been developing nanoparticles with neutrophil trophism that home to the sites of infection via these first-responder leukocytes, named neutrophil-avid nanocarriers (NANs). Here, we demonstrate that human neutrophils can phagocytose nanogels (NGs), a type of NAN, with enhanced uptake after particle serum opsonization, comparing neutrophils from healthy individuals to those with STAT3 HIES, where both groups exhibit NG uptake; however, the patient group showed reduced phagocytosis efficiency with serum-opsonized NANs. Proteomic analysis of NG protein corona revealed complement components, particularly C3, as predominant in both groups. Difference between groups includes STAT3 HIES samples with higher neutrophil protein and lower acute-phase protein expression. The study suggests that despite neutrophil dysfunction in STAT3 HIES, NANs have potential for directed delivery of cargo therapeutics to improve neutrophil infection clearance.

Genetic Evaluation of Patients Suspected of Immunodeficiency Referred to the Immunodeficiency Clinic of Akbar Hospital in Mashhad

Background: The purpose of this study was genetic evaluation of patients suspected of immunodeficiency, without a definitive diagnosis, referred to the Immunodeficiency Clinic of Akbar Hospital in Mashhad in 2021-2022. Methods: In this study, patients suspected of immunodeficiency, without a definitive diagnosis, referred to an immunodeficiency clinic were included A complete clinical and paraclinical examination has been done by expert specialists and clinical geneticists. Blood samples were taken for genetic analysis using the Exome Sequencing technique followed by comprehensive bioinformatics analysis. Parents and healthy offspring were assessed for the candidate gene variants. Results: In this study, 185 patients were included; 58.56% of them were male; The average age of the participants was 9.28±5.40 years, and consanguineous marriage of parents was observed in 79.8 % of cases. Pneumonia with 33.51% was the most common clinical manifestation in patients with suspected immunodeficiency. In total, 41.14% of patients suffered from combined immunodeficiency, 26 .86% of them had defects of phagocyte number, function, or both; and 24% had predominantly antibody deficiencies. Hyper IgE syndrome was detected in 16% of patients, SCID and CGD each in 14.86% of patients, CVID in 12% of patients, and LAD in 7.43% of them. In 37.04% of the identified genes, there was a discrepancy between clinical and genetic diagnosis in patients. Conclusion: The most common clinical manifestation of patients suspected of primary immunodeficiency is pneumonia; therefore, patients who suffer from recurrent respiratory infections should be checked for genetic immunodeficiency. In this study, most patients were in the groups of immunodeficiencies affecting multiple cell types, defects of phagocyte number, function, or both; and predominantly antibody deficiencies, respectively. The most common diseases diagnosed were: Hyper IgE syndrome, SCID and CGD, CVID, and LAD.

Hyper IgE Syndromes.

The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels. Nowadays a geneticmolecular characterization is possible and allows the distinction in various monogenic pathologies, which share some clinical characteristics but also important differences. In addition to long-known STAT3 and DOCK8 gene mutations, in fact, also ZNF341, CARD11, ERBB2IP, IL6R and IL6ST genes mutations can cause the disease. The main clinical manifestations are represented by newborn rash, eczema similar to atopic dermatitis, bacterial and viral skin infections, cold abscesses, respiratory infections with possible pulmonary complications, allergies, gastrointestinal manifestations, malignancies and connective tissue abnormalities. Diagnosis is still a challenge because, especially in the early stages of life, it is difficult to distinguish from other pathologies characterized by eczema and high IgE, such as atopic dermatitis. Several scores and diagnostic pathways have been developed, but it is essential to seek a genetic diagnosis. Treatment is based on prevention and early treatment of infections, meticulous skincare, intravenous immunoglobulins and HSCT, which, in some HIES subtypes, can modify the prognosis. Prognosis is related to the affected gene, but also to early diagnosis, timely treatment of infections and early HSCT.

Immunoglobulin class-switch recombination: Mechanism, regulation, and related diseases.

Maturation of the secondary antibody repertoire requires class-switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high-affinity antibodies. Following immune response or infection within the body, activation of T cell-dependent and T cell-independent antigens triggers the activation of activation-induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper-IgM syndrome, Waldenström macroglobulinemia, hyper-IgD syndrome, selective IgA deficiency, hyper-IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.

Identifying potentially undiagnosed individuals with hyper-IgE syndrome using a scoring system

BackgroundHyper-IgE syndrome (HIES) constitutes a group of rare primary immunodeficiency disorders. The diagnosis relies on the National Institutes of Health (NIH) scoring system, incorporating clinical and laboratory data. Scores greater than or equal to 15 raise a strong suspicion of the disease. In an isolated Israeli population, Zinc Finger 341 deficiency, a subtype of HIES, has a carrier incidence of 1:20, but the prevalence of the clinical syndrome within this community remains unknown. ObjectiveTo estimate the prevalence of potentially undiagnosed HIES cases within this population by using the NIH scoring criteria. MethodsThis retrospective cohort study obtained requisite clinical and laboratory data for NIH score computation from the electronic medical records of Clalit Health Services for the isolated village under scrutiny in comparison to a neighboring village. Subsequently, clinical scores were assigned to each subject, enabling comparative analysis of suspected diagnosis rates between the 2 populations. ResultsAmong the 29,390 studied subjects, 12 had a documented diagnosis of HIES. All were in the study village, and none were from the control village (0.08% vs 0%, P < .01). Within the study village, 235 individuals (1.62%) had an NIH score greater than or equal to 15 and were suspected with having HIES almost doubled compared with the control group at 130 individuals (0.87%) (P < .001). ConclusionThis is the first time the NIH clinical score system has been used for population screening. The significant disparity in the prevalence of suspected, undiagnosed cases between the study village and the control village strongly suggests the potential utility of this tool for preliminary screening.

Obstructive uropathy in STAT 3 hyper immunoglobulin E syndrome: A 5year old Middle Eastern boy.

Autosomal dominant hyper immunoglobulin E (IgE) syndrome is a rare inborn error of immunity that affects approximately one in a million individuals worldwide. It presents with various symptoms owing to multisystem involvement (immunological and non-immunological). Recurrent infections (mainly in the skin and lungs) are common presentations. A 5-year-old Middle Eastern boy presented with symptoms suggestive of obstructive uropathy secondary to multiple large pelviabdominal abscesses and acute kidney injury with hyperkalemia that necessitated admission to the intensive care unit. Upon further investigation, the patient's genetic test (whole exome sequencing) demonstrated a heterozygous missense variant in the STAT3 gene. The patient completely recovered and did not require further admission after initiating prophylactic antibiotics. Although deep-seated infections are uncommon in STAT3 hyper IgE syndrome, skin and lung infections are most commonly observed. Multiple deep collections can occur and require prompt intervention and aggressive treatment.

Low incidence of primary immunodeficiency-associated cancers in children at a tertiary care pediatric hospital in Pakistan: a blessing in disguise or wet behind the ears?

Scarce data is available regarding primary immunodeficiency-associated cancers in children in low-middle-income countries. This study aimed to determine the incidence, clinical features and outcomes of primary immunodeficiencies (PIDs)-associated cancers in children presenting to Pakistan's largest public-sector specialised pediatric oncology center. Among 5,748 children with cancers registered over 5 years, only eight patients were found to have PID-associated pediatric malignancies with an incidence of 1.4 per 1,000 cases. The median age at the time of diagnosis was 6.5 years with a male-to-female ratio of 7:1. Only four types of PIDs were found to be associated with cancer in children at our center: Ataxia Telangiectasia in 37.5% (n = 3), hyper-IgE syndrome and IgG deficiency in 25% (each n = 2) and one case (12.5%) of common variable immune deficiency. Six different types of pediatric cancers were associated with PID with a predisposition towards hematological malignancies (n = 7, 87.5%). Only two patients (25%) survived. The median survival of the cohort was 3.5 months. Infection-related mortality was the cause of death in four patients (66%), and the type of PID was the only statistically significant factor associated with the outcome. It is concluded that a lesser proportion of PID-associated pediatric cancers are found in our center as compared to the reported data from high-income countries. PID-associated cancers in children have an abysmal prognosis and infection-related mortality is the major cause of treatment failure. Sensitisation of oncologists to look for any underlying PID, the introduction of PID-screening programs in children and consideration of PID-associated malignancies as a high-risk group for treatment may help improve the outcomes.

Allergic fungal rhinosinusitis linked to other hyper-IgE syndromes through defective TH17 responses

BackgroundIn a gene expression analysis comparing sinus mucosa from allergic fungal rhinosinusitis (AFRS) to that from non-AFRS chronic rhinosinusitis with nasal polyp (CRSwNP) subjects, the antimicrobial peptide (AMP), histatin 1 (HTN1), was found to be the most differentially down-regulated gene in AFRS. ObjectiveTo identify the molecular etiology of the down regulated expression of HTN1 MethodsWe used RT-PCR to compare the expression of AMPs and utilized a fungistasis assay to evaluate the anti-fungal activity of sinus secretions. Using flow cytometry, we characterized the presence of Th17/22 cells and STAT signaling from AFRS, non-AFRS CRSwNP patients, and healthy controls. ResultsWe confirm the decreased expression of AMPs in AFRS sinus mucosa with concordant decrease in antifungal activity in sinus secretions. We show that IL-22 and IL-22-producing T cells are deficient within sinus mucosa of AFRS subjects. 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. ConclusionSimilar 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.

PA03 Should patients with atopic dermatitis be screened for genes associated with hyper-IgE syndrome?

PA03 Should patients with atopic dermatitis be screened for genes associated with hyper-IgE syndrome?

A term infant with severe hypereosinophilia secondary to CMV infection and the STAT1 gene mutation: a case report

Hypereosinophilia is a rare presentation in all age groups, particularly when it is severe, persistent, and progressive. We describe the clinical characteristics and course of severe hypereosinophilia in a full-term Saudi female neonate. A febrile respiratory illness evolved with a progressive increase in peripheral blood leukocyte and eosinophil counts, reaching 44.9% of leukocytes and an absolute value of 57,000 cells/µl. Different etiological examinations (for viral, bacterial, immunodeficiency, hyper IgE syndrome, gene mutations) revealed extremely high CMV antigenemia and a homozygous mutation in the STAT1 gene. Anhelation was relieved by oxygen and anti-viral treatment. Steroids brought a dramatic response in peripheral blood counts within 24 h. After a 6-week course of antiviral and steroid treatment at home, she had an excellent general condition. Conclusion: Although a rare pathology, it is important to consider genetic disorders when there is an atypical immune response to viral infections.

Hyper IgE syndrom suspect - Case Report

Introduction: Hyper IgE syndrome (HIES) is a rare condition of the immune system characterized by various types of infections throughout life. This syndrome can be divided into two types, dominant heterozygous related to STAT3 gene mutation and recessive homozygous, which can also be subdivided into two groups related to Tyk2 and DOCK8 gene mutations, each presenting variations in their clinical presentations. Diagnosis is based on genetic sequencing, although there are some symptoms, clinical factors, and hereditary factors that can assist in diagnosis. There is no specific treatment for this pathology, with the main focus being on controlling infections and infusing immunological therapies such as intravenous immunoglobulin G.

Viral infections and inborn errors of immunity.

The purpose of this focused review is to discuss unusual presentations of viral infections in the context of specific inborn errors of immunity. We will discuss hyper immunoglobulin E (IgE) syndromes, epidermodysplasia verruciformis, and X-linked agammaglobulinemia as examples of inborn errors of immunity associated with specific presentations of viral infection and disease. Advances in both genetic and viral diagnostics have broadened our understanding of viral pathogenesis in the setting of immune dysfunction and the variable phenotype of inborn errors of immunity. Dedicator of cytokinesis 8 (DOCK8) deficiency is now recognized as an inborn error of immunity within the hyper IgE syndrome phenotype and is associated with unusually aggressive cutaneous disease caused by herpes simplex and other viruses. Studies of patients with epidermodysplasia verruciformis have proven that rarely detected human papillomavirus subtypes may cause malignancy in the absence of adequate host defenses. Finally, patients with X-linked agammaglobulinemia may remain at risk for severe and chronic viral infections, even as immune globulin supplementation reduces the risk of bacterial infection. Susceptibility to viral infections in patients with inborn errors of immunity is conferred by specific, molecular defects. Recurrent, severe, or otherwise unusual presentations of viral disease should prompt investigation for an underlying genetic defect.

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.