hyper-IgE Research Articles

THE EVALUATION AND MANAGMENT OF DOCK8 DEFICIENCY

Introduction We present a case involving a child with a complex medical history who presented with a one-day history of fever, facial swelling, and skin rash. Case Description Our patient is a 2-year-old male with history of eczema, failure to thrive, chronic lymphadenopathy, developmental delay, and food allergies who presented with a one-day history of fever, facial swelling, and eczema. Physical examination was notable for an ill appearing child with coarse facial features. He had perioral edema, skin lichenification, diffuse eczematous rash, and chronic lymphadenopathy. Labs were notable for leukocytosis and elevated inflammatory markers. Skin and conjunctival cultures were positive for Herpes Simplex Virus. Wound cultures were positive for methicillin-resistant Staphylococcus aureus. He was treated with acyclovir, vancomycin, cefoxitin, and mupirocin ointment. The lab results from hospitalization were obtained. The hyper-IgE panel revealed a homozygous mutation in the DOCK8 gene which is located within one of the regions of homozygosity identified on SNP microarray diagnosing him with DOCK8 deficiency. Discussion This case demonstrates that DOCK8 deficiency should be included in the differential diagnosis involving children with eczema, failure to thrive, and cutaneous infections. Our patient had coarse facial features, however, this is not a common feature of DOCK8 deficiency. The study, Cutaneous Manifestations of DOCK8 Deficiency Syndrome, evaluated the clinical features of Job Syndrome and DOCK8 deficiency and found that in DOCK8 deficiency, coarse facial features were not present. Our case report shows that the presence of coarse facial features should not necessarily exclude DOCK8 deficiency.

Eosinophilia and reduced STAT3 signaling affect neutrophil cell death in autosomal-dominant Hyper-IgE syndrome.

The autosomal‐dominant hyper‐IgE syndrome (HIES), caused by mutations in STAT3, is a rare primary immunodeficiency that predisposes to mucocutaneous candidiasis and staphylococcal skin and lung infections. This infection phenotype is suggestive of defects in neutrophils, but data on neutrophil functions in HIES are inconsistent. This study was undertaken to functionally characterize neutrophils in STAT3‐deficient HIES patients and to analyze whether the patients` eosinophilia affects the neutrophil phenotype in S. aureus infection. Neutrophil functions and cell death kinetics were studied in eight STAT3‐deficient patients. Moreover, the response of STAT3‐deficient neutrophils to S. aureus and the impact of autologous eosinophils on pathogen‐induced cell death were analyzed. No specific aberrations in neutrophil functions were detected within this cohort. However, the half‐life of STAT3‐deficient neutrophils ex vivo was reduced, which was partially attributable to the presence of eosinophils. Increased S. aureus‐induced cell lysis, dependent on the staphylococcal virulence controlling accessory gene regulator (agr)‐locus, was observed in STAT3‐deficient neutrophils and upon addition of eosinophils. Accelerated neutrophil cell death kinetics may underlie the reported variability in neutrophil function testing in HIES. Increased S. aureus‐induced lysis of STAT3‐deficient neutrophils might affect pathogen control and contribute to tissue destruction during staphylococcal infections in HIES.

Quantitative profiling of cytokines and chemokines in DOCK8-deficient and atopic dermatitis patients.

Hyper-IgE syndromes (HIES) are a clinically overlapping, heterogeneous group of inborn errors of immunity characterized by elevated serum IgE level, eosinophilia, atopy, and immune dysregulation. Deficiency of DOCK8 protein is potentially a life-threatening autosomal recessive HIES and only curable with bone marrow transplantation. Hence, the diagnosis of DOCK8 deficiency is critical and should be sought at an early stage to initiate definitive therapy. Serum samples from patients with DOCK8 deficiency and atopic dermatitis were profiled on a cytokine/chemokine panel for potential differential expression. CXCL10 and TNF-A were upregulated in DOCK8 patients when compared to AD, possibly contributing toward increased susceptibility to infections and cancer. In contrast, epidermal growth factor (EGF) was significantly downregulated in a subgroup of DOCK8-deficient and AD patients, while IL-31 expression was comparable between both DOCK8-deficient and AD cohorts, possibly contributing toward pruritus seen in both groups. This comprehensive cytokine profile in HIES patients reveals distinctive biomarkers that differentiate between the DOCK8-deficient and AD patients. The unique expression profile of various inflammatory cytokines in patients with DOCK8 deficiency vs atopic dermatitis likely reflects disease-specific perturbations in multiple cellular processes and pathways leading to a predisposition to infections and allergies seen in these patients. These data agree with the role for EGF replacement therapy in EGF-deficient individuals with AD as well as DOCK8 deficiency through a potential shared pathway. In addition, these novel biomarkers may be potentially useful in distinguishing DOCK8 deficiency from AD allowing early-targeted treatment options.

Hyper-IgE in the allergy clinic--when is it primary immunodeficiency?

The 2017 International Union of Immunological Societies (IUIS) classification recognizes 3 hyper-IgE syndromes (HIES), including the prototypic Job's syndrome (autosomal dominant STAT3-loss of function) and autosomal recessive PGM3 and SPINK5 syndromes. Early diagnosis of PID can direct life-saving or transformational interventions; however, it remains challenging owing to the rarity of these conditions. This can result in diagnostic delay and worsen prognosis. Within increasing access to "clinical-exome" testing, clinicians need to be aware of the implication and rationale for genetic testing, including the benefits and limitations of current therapies. Extreme elevation of serum IgE has been associated with a growing number of PID syndromes including the novel CARD11 and ZNF341 deficiencies. Variable elevations in IgE are associated with defects in innate, humoral, cellular and combined immunodeficiency syndromes. Barrier compromise can closely phenocopy these conditions. The aim of this article was to update readers on recent developments at this important interface between allergy and immunodeficiency, highlighting key clinical scenarios which should draw attention to possible immunodeficiency associated with extreme elevation of IgE, and outline initial laboratory assessment and management.

One-lung Ventilation in a Child with Hyper-IgE Syndrome

1. Abstract A four years old female affected by AD-HIES was hospitalized for streptococcal right pneumonia with pleural effusion and pneumatocele. Despite multiple antibiotic therapy and Igev she developed massive right hydropneumothorax. Pleural drainage was positioned, and surgical toilette was done. A conservative approach with one-lobe ventilation, chosen in order to allow pleural healing, caused the re-expansion of right lung. STAT3 mutation leads likely to pyogenic pneumonia and to abnormalities in tissue remodeling after surgical intervention, so a conservative approach is recommended. In our case prolonged antibiotic therapy, chest drainage and one lung ventilation allowed to avoid pneumonectomy preserving respiratory function. 2. Keywords: <span style=font-size:10.0pt;font-family: times= new= roman,serif=> <span style=font-size:10.0pt;font-family: times= new= roman,serif=>Hyper-IgE syndrome; One lung ventilation; Pneumococcal pneumonia; Pneumothorax

Phenotyping and long-term follow up of patients with hyper IgE syndrome

Introduction and objectivesLong-term follow up of patients with hyper IgE syndrome (HIES), as a primary immunodeficiency disorder, has been poorly investigated. This study describes common clinical and immunological features of patients with HIES in the last 10 years in Shiraz University of Medical Sciences, Shiraz, Iran. Methods and patientsIn this cross-sectional study, the symptoms and medical records of 18 patients, who were diagnosed with HIES, were observed. Genetic and immunologic study was also performed. ResultsEighteen patients with the mean age of 13 years old were investigated. Ten patients were detected to have mutations in DOCK8 gene and autosomal recessive HIES (AR-HIES); and four patients were found with STAT3 mutation and autosomal dominant HIES (AD-HIES). So, 14 patients with known genetic results were considered for further data analysis. Food allergy, eczema, viral and skin infections were the major complications of AR-HIES patients. The major clinical complications of AD-HIES patients were pneumonia, skin infections and eczema. Food allergy and viral infection were significantly higher in DOCK8 deficient patients. The most common causes of hospitalization in both AR-HIES and AD-HIES patients were pneumonia, skin infections and sepsis. The most common cause of death was found to be sepsis. ConclusionsAD-HIES and AR-HIES cannot be differentiated only based on the clinical presentations. Genetic features are also necessary for better diagnosis. This study, summarizing the clinical, immunological and genetic information of the patients with AD-HIES and AR-HIES, may open a way for better diagnosis and management of HIES.

Human defects in STAT3 promote oral mucosal fungal and bacterial dysbiosis.

Studies in patients with genetic defects can provide unique insights regarding the role of specific genes and pathways in humans. Patients with defects in the Th17/IL-17 axis, such as patients harboring loss-of-function STAT3 mutations (autosomal-dominant hyper IgE syndrome; AD-HIES) present with recurrent oral fungal infections. Our studies aimed to comprehensively evaluate consequences of STAT3 deficiency on the oral commensal microbiome. We characterized fungal and bacterial communities in AD-HIES in the presence and absence of oral fungal infection compared with healthy volunteers. Analyses of oral mucosal fungal communities in AD-HIES revealed severe dysbiosis with dominance of Candida albicans (C. albicans) in actively infected patients and minimal representation of health-associated fungi and/or opportunists. Bacterial communities also displayed dysbiosis in AD-HIES, particularly in the setting of active Candida infection. Active candidiasis was associated with decreased microbial diversity and enrichment of the streptococci Streptococcus oralis (S. oralis) and S. mutans, suggesting an interkingdom interaction of C. albicans with oral streptococci. Increased abundance of S. mutans was consistent with susceptibility to dental caries in AD-HIES. Collectively, our findings illustrate a critical role for STAT3/Th17 in the containment of C. albicans as a commensal organism and an overall contribution in the establishment of fungal and bacterial oral commensal communities.

Poster 246: Syringomyelia in a Patient with Job Syndrome

PM&RVolume 10, Issue 9S1 p. S82-S82 Poster 246: Syringomyelia in a Patient with Job Syndrome Caroline A. Schepker DO, Caroline A. Schepker DO New York Presbyterian Hospital, Columbia, New York, NY, United StatesSearch for more papers by this authorAkinpelumi Beckley MD, MBA, Akinpelumi Beckley MD, MBASearch for more papers by this author Caroline A. Schepker DO, Caroline A. Schepker DO New York Presbyterian Hospital, Columbia, New York, NY, United StatesSearch for more papers by this authorAkinpelumi Beckley MD, MBA, Akinpelumi Beckley MD, MBASearch for more papers by this author First published: 26 September 2018 https://doi.org/10.1016/j.pmrj.2018.08.258Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume10, Issue9S12018 AAPM&R Annual Assembly AbstractsSeptember 2018Pages S82-S82 RelatedInformation

Clinical Manifestation of Hyper IgE Syndrome Including Otitis Media.

The hyper IgE syndromes (HIES) comprise a group of rare primary immunodeficiency disorders (PIDDs), which are characterized by extremely high serum IgE levels, eczema, recurrent skin and pulmonary infections. Both autosomal dominant (AD) HIES due to STAT3 mutations and autosomal recessive (AR) HIES due to PGM3, SPINK5, DOCK8 and TKY2 mutations have been reported. Here, we aim to summarize and compare the major clinical manifestations of different subtypes of HIES. We will also discuss otitis media, which usually do not get enough attention in HIES. Update and familiarity with these clinical features will help to make a better diagnose, assessment and treatment of HIES. Although hyper serum IgE levels have been identified in PGM3 deficiency and Comel-Netherton syndrome, PGM3 and SPINK5 genes were not included in the list of genetic etiologies of AR-HIES by the Expert Committee of the International Union of Immunological Societies until 2015. The identification of these HIES-causing genes greatly promoted the pathogenic mechanism studies of HIES. Also, in recent years, more clinical manifestations, which were often not of concern in HIES patients, have been shown to be highly related to HIES. For example, a significantly high frequency of vascular and gastrointestinal abnormities has been reported in STAT3-deficient AD-HIES patients. These new findings might help to provide new clues to the functional study of these HIES-related genes. This review summarizes and compares the major clinical manifestations of different subtypes of HIES, and we suggest that the incidence and severity of otitis media should not be underestimated in HIES patients.

Chronic rhinosinusitis with severe nasal polyposis in hyper-IgE syndrome

Chronic rhinosinusitis with severe nasal polyposis in hyper-IgE syndrome

Voriconazole-induced phototoxicity, malignancy, and periostitis in a child with autosomal dominant hyper-IgE syndrome

Voriconazole-induced phototoxicity, malignancy, and periostitis in a child with autosomal dominant hyper-IgE syndrome

Human hyper-IgE syndrome: singular or plural?

Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term "HIES" to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

Adrenal Suppression Secondary to Interaction of Combined Inhaled Corticosteroid and Antifungal Agent

Objective: Inhaled corticosteroids (ICS) are exogenous glucocorticoids that typically have minimal systemic effects at standard doses. They are metabolized by the cytochrome P450 (CYP450) enzyme pathway in the liver; thus, they can cause unwanted side effects when used in conjunction with medications affecting this system. Here, we present a case of adrenal suppression (AS) secondary to combined usage of ICS and posaconazole, a known CYP450 inhibitor. Methods: Clinical and laboratory data were isolated and are presented. Results: A 9-year-old Caucasian female with history of hyper IgE syndrome. On chronic fluticasone and posaconazole for Aspergillus infection, she presented with fatigue and “facial puffiness” (cushingoid features). Low morning cortisol (0.3 μg/dL) prompted further evaluation. Low-dose (1 μg) adrenocorticotropic hormone (ACTH)-stimulation test with peak cortisol level <1 μg/dL. Other causes of hypocortisolism were ruled out. Started on physiologic hydrocortisone (10 mg/m2/day) and fluticas...

Multiplexed detection of DOCK8, PGM3 and STAT3 proteins for the diagnosis of Hyper-Immunoglobulin E syndrome using gold nanoparticles-based immunosensor array platform

Multiplexed biosensors hold great promise for early diagnosis of diseases where the detection of multiple biomarkers is required. Hyper Immunoglobulin E syndromes (HIES) are rare primary immunodeficiency disorders associated with mutations either in the signal transducer and activator of transcription 3 (STAT3), dedicator of cytokinesis 8 DOCK8) or phosphoglucomutase 3 (PGM3) genes. Yet, the diagnosis of HIES is challenged by the complexity of the existing laboratory assays. Here, we report for the first time the development of a multiplexed electrochemical immunosensor for the simultaneous detection of DOCK8, STAT3 and PGM3 proteins. The immunosensor was constructed on carbon array electrodes that were first modified by electrodeposition of gold nanoparticles (AuNPs). The array electrodes were then used to immobilize specific antibodies for the three proteins after the functionalization of the electrodes with cysteamine/glutaraldehyde linkers. The simultaneous detection of the DOCK8, PGM3 and STAT3 proteins was successfully realized by the immunosensor with respective limits of detections of 3.1, 2.2 and 3.5 pg/ml. The immunosensor has shown good sensitivity as well as selectivity against other proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and Duchenne Muscular Dystrophy (DMD). Moreover, the immunosensor was successfully applied in human serum samples showing capability to distinguish the HIES from the control samples.

Deciphering the relevance of a new gene for Hyper IgE syndrome

Deciphering the relevance of a new gene for Hyper IgE syndrome

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

Rheumatological manifestations in primary immunodeficiency diseases

Primary immune deficiencies (PIDs) are characterized by quantitative and/or functional abnormalities of the immune system elements. Bone and joint abnormalities are not rare in patients with immunodeficiencies. Joint manifestations, of which arthritis is the most common, occur mainly in humoral PIDs (X-linked agammaglobulinemia, common variable immunodeficiency, and IgA deficiency) and occasionally in defects of the phagocyte system (chronic granulomatous disease, glicogen storage diseases). Monoarthritis or oligoarthritis is the usual pattern, caused by Mycoplasma, Staphylococcus, Streptococcus, Pneumococcus or Haemophilus species. These bacteria can provoke not only synovial infections, but also aseptic arthritogenic inflammatory responses. Infectious arthritis or osteomyelitis must be diagnosed and treated with antimicrobial therapy at the earliest. Bone lesions are far less common and usually present as infectious complications in humoral PID. Larger bone manifestations occur in hyper-IgE syndrome and spondyloepiphyseal dysplasia. Short stature is the most common in reticular dysgenesis, in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia and in DNA repair disorders. Knowledge of PID syndromes both enhances the diagnostic capabilities of physicians and provides understanding the pathophysiology of bone and joint abnormalities associated with immune dysfunction. In children and occasionally in adults, a combination of bone and/or joint manifestations and hypogammaglobulinemia may be the first sign of PID. When lymphoproliferative disease or infection can not be proved, investigations for PID should be accomplished. Orv Hetil. 2018; 159(23): 918-928.

Toll-like receptors in B cell activation and STAT3 signal pathway

Toll-like receptors(TLR)are widely exist in antigen presenting cells as a kind of pattern recognition receptor involved in the recognition of molecular structures specific for microbial pathogens, and have an important effect on innate and adaptive immune responses.There are 10 types of TLR in human beings which can be grouped into two main categories: cell surface receptors and receptors localized in the endosome.Among all the TLRs, TLR7 and TLR9, which expressed widely in human B cells, are important to B cells′ functions.Two signal transduction pathways of TLR including MyD88 pathway and non-MyD88 pathway associate with B cells activation, proliferation, differentiation and antibody secretion.TLR7 and TLR9′s stimulus, such as CpG-containing oligodeoxynucleotides(ODN)can activate memory B cells and naive B cells, promote cells proliferation, plasma cells generation, cytokine secretion and protect them from apoptosis.More than that, TLR7 and TLR9 can stimulate the production of IgG and IgM, make antibody shift to IgG2a and block the production of IgG1 and IgE.Interestingly, TLR-MyD88 pathway is recently confirmed to have connection with STAT3 signal pathway.However, the mutation of STAT3 will cause autosomal dominant hyper-IgE syndrome(HIES), a primary immunodeficiency characterized by elevated IgE levels, eczema, recurrent infections, pneumonia as well as multi-system symptoms.Therefore, the pathogenesis of HIES maybe related to the inhibition of TLR-MyD88-STAT3 signal pathway.As a result, we write a review about TLR in B cell activation and STAT3 signal pathway, and discuss their connection between HIES. Key words: TLR; TLR9; B cell functions; STAT3; Hyper-IgE syndrome

STAT3-Mediated Transcriptional Regulation of Osteopontin in STAT3 Loss-of-Function Related Hyper IgE Syndrome.

Hyper-IgE syndrome (HIES) caused by loss-of-function (LOF) mutations in STAT3 gene (STAT3 LOF HIES) is associated with dental and facial abnormalities in addition to immunological defects. The role of STAT3 in the pathogenesis of the dental/facial features is, however, poorly elucidated. Since mechanism of cellular resorption of mineralized tissues such as bone and teeth are similar, we attempted to study the expression of genes involved in bone homeostasis in STAT3 LOF HIES. Peripheral blood mononuclear cells from healthy controls (HCs), STAT3 LOF HIES patients, STAT3-/- PC-3 cells and STAT3+/+ LNCaP cells were stimulated with IL-6 and quantitative PCR array was performed to study the relative mRNA expression of 43 pre-selected genes. PCR array finding were further evaluated after stattic induced STAT3 inhibition. Osteopontin (OPN) gene was seen to be significantly upregulated after IL-6 stimulation in HC (mean fold change 18.6, p = 0.01) compared with HIES subjects. Inhibition of STAT3 signaling by stattic followed by IL-6 stimulation abrogated the OPN response in HCs suggesting that IL-6-induced STAT3 signaling regulates OPN expression. Bioinformatics analysis predicted the presence of STAT3 response element TTCCAAGAA at position -2005 of the OPN gene. Regulation of OPN gene through IL-6-mediated STAT3 activation and its significant dysregulation in STAT3 LOF HIES subjects could make OPN a plausible candidate involved in the pathogenesis of dental/facial manifestations in HIES.

Development of Impedimetric Immunosensors for the Diagnosis of DOCK8 and STAT3 Related Hyper-Immunoglobulin E Syndrome

Hyper Immunoglobulin E syndrome (HIES) is a rare inherited inborn error of primary immunodeficiency. HIES is characterized by high levels of serum immunoglobulin E (IgE), severe eczema, which overlap with atopic dermatitis, as well as lung infections and even death. HIESs are genetically inherited by heterozygous or homozygous mutations in signal transducer and activator of transcription 3 (STAT3) or Dedicator of cytokinesis 8 (DOCK8) genes, in autosomal dominant and recessive forms, respectively. Therefore, the early detection of DOCK8 and STAT3 protein levels in humans would facilitate the early diagnosis of these disorders and thus, help in the disease management. Here, we present the development of immunosensors for the detection of DOCK8 and STAT3 using electrochemical impedance spectroscopy in a label-free format. The immunosensors were fabricated by the covalent attachment of specific antibodies for DOCK8 and STAT3 on gold electrodes via cysteamine/phenylene diisothiocyanate linkers. The detection was achieved by monitoring the change in the charge transfer resistance (R-ct) of ferro/ferricyanide redox couple upon binding of the proteins to the immunosensor surface. These biosensors enabled the detection of DOCK8 and STAT3 levels with low detection limits of 1.2 and 9.0pg/ml, respectively. The immunosensor was also applied for the detection of DOCK8 in human serum samples showing high recovery percentages which indicates great promise of this method for early diagnosis of HIES in newborn infants.