hyper-IgE Research Articles

Correction: Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Correction: Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Thoracic Manifestations of Primary Immunodeficiency Disorders.

Primary immunodeficiency disorders (PIDD) are a group of disorders presenting with recurrent infections. The authors retrospectively reviewed the imaging records of 24 proven cases of PIDD and correlated the imaging findings with the type of defect. Final diagnoses were categorized in four groups; Group I (humoral immunodeficiency), Group 2 (cell mediated immunodeficiency), Group 3 (phagocytic disorders) and Group 4 (others). Group 3 was the commonest, followed by 1 and 2. Three most common disorders encountered were chronic granulomatous disease (CGD) (7/24), hyper IgE syndrome (5/24) and common variable immunodeficiency (CVID) (4/24). Consolidation (12/24), nodules (10/24), bronchiectasis (9/24) and lymphadenopathy (8/24) were the commonest imaging findings. Although not statistically significant, some definite imaging trends could be established. Presence of consolidation and nodules; with absence of bronchiectasis was the striking finding in Group 3. Group 2 disorders predominantly showed bronchiectasis, whereas presence of consolidation, nodules, bronchiectasis all were very common in Group 1.

The effects of germline STAT3-activating mutations from autoimmunity and lymphoid malignancy on mouse and human T cells

Abstract Signal transducer and activator of transcription 3 (STAT3) regulates gene expression downstream of cell surface cytokine and hormone receptors. Heterozygous germline loss of function STAT3 mutations lead to the primary immunodeficiency hyper-IgE syndrome while somatic activating STAT3 mutations recur in human solid organ and immune malignancies. Germline heterozygous activating STAT3 mutations result in early-onset autoimmunity with aspects of immunodeficiency. Affected individuals share characteristics with autoimmune lymphoproliferative syndrome and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, including reduced T regulatory cell numbers. They present with variable autoimmune symptoms including type 1 diabetes, rheumatoid arthritis, gut enteropathies and autoimmune cytopenias. Whilst many effects of STAT3 loss of function on immune cells have been described, the mechanisms behind autoimmunity and immunodeficiency in patients with activating STAT3 mutations remain unclear. Here, we present a detailed characterisation of T cell development and maturation in young and old mice on two different backgrounds with Crispr-engineered germline activating mutations in two domains of STAT3. We use mixed chimeras, flow cytometry, T cell receptor deep sequencing and high throughput single-cell transcriptomics to reveal cell-extrinsic and -autonomous roles of overactive STAT3 in T cells in autoimmunity and immune malignancy. To our knowledge, this is the first report of mice with Stat3 germline activating mutations identical to those in autoimmunity or malignancy. We validate our key findings in humans with gain of function germline STAT3 mutations and childhood-onset autoimmunity.

Autosomal dominant hyper IgE syndrome from a single centre in Chongqing, China (2009-2018).

Autosomal dominant hyper IgE syndrome (AD-HIES) caused by STAT3 gene mutation is a rare primary immunodeficiency disease. To better understand the disease, we described the clinical characteristics of 20 AD-HIES patients in Chongqing, China and explored the effect of mutations in different domains of STAT3 gene on the function of STAT3 protein by Western blot and confocal microscopy. The mean age at onset was 0.12years. The mean age at diagnosis was 5.31years. The most common presentation was eczema, pneumonia, skin abscesses and chronic mucocutaneous candidiasis. Seven patients suffered from BCG complications. R382W/Q were identified in 12 patients, V637M mutation in three patients. Three patients have died. The phosphorylated STAT3 was expressed more in wild-type(WT) and R382W mutant STAT3 in the cytoplasm of COS7 cells with epidermal growth factor(EGF) stimulation, less in the V637M mutation and T620S mutation. Dynamic observation showed that STAT3 cytoplasmic accumulation and nuclear translocation occurred rapidly after EGF stimulation in WT-STAT3-GFP, the time of accumulation and nuclear translocation was later and the expression was less in R382W-STAT3-GFP compared with WT-STAT3-GFP, followed by V637M and T620S mutation. These results suggested that our patients had earlier onset, diagnostic age and higher rate of BCG complications. However, our patients had higher incidence of mortality though the earlier diagnostic age. We did not find a significant genotype/phenotype correlation, but Src homology 2 domain mutations (V637M and T620S) had a greater effect on STAT3 phosphorylation and nuclear translocation than DNA-binding domain mutation (R382W) in vitro.

Late onset Job syndrome With Growth Retardation

A 9-year-old girl presented with severe eczematous lesions and multiple infections since age of 6 year with growth retardation and raised serum IgE levels, suggestive of Job syndrome. The unusual late onset of clinical manifestations of the disease is highlighted.

Chronic Rhinosinusitis in Pediatric Immunodeficiency

Chronic rhinosinusitis and other sinopulmonary infections can be a hallmark of impaired immunity in children. Rhinosinusitis in the setting of immunodeficiency can often be chronic and refractory, and involve opportunistic pathogens. We review the evaluation and management of pediatric chronic rhinosinusitis in the context of primary immunodeficiency diseases. Immunodeficiencies found to be associated with chronic rhinosinusitis include common variable immune deficiency, X-linked agammaglobulinemia, antibody deficiencies, hyper-IgM syndrome, hyper-IgE syndrome, Wiskott–Aldrich syndrome, activated PI3K disease, DiGeorge syndrome, and chronic granulomatous disease. Chronic rhinosinusitis in children may be a clinical manifestation of immunodeficiency. The evaluation and diagnosis of immunodeficiencies are essential for initiating appropriate therapeutic strategies, including antibiotics, prophylaxis, topical therapy, surgery, and immunoglobulin replacement.

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Immunodeficiency diseases with interstitial lung disease as major clinical manifestations: report of six cases

Objective: To summarize the clinical features of immunodeficiency diseases with interstitial lung disease (ILD) as major clinical manifestations and to improve understanding etiology of ILD. Methods: The clinical features and clinical clues for diagnosis of six cases with immunodeficiency presented with ILD in Shenzhen Children's Hospital from January 2014 to December 2016 were retrospectively analyzed. Results: The patients' age ranged from 3 months to 5 years and 9 months, 5 cases were male. All cases had cough and tachypnea, 3 cases had lung infection and respiratory failure, 2 cases had chronic hypoxia and one had clubbing. Three cases had skin rashes; 5 cases had failure to thrive. Chest CT scan showed diffuse ground glass opacity in all the 6 cases, and 2 cases had cystic changes and one had "crazy-paving" pattern. Five patients were suspected to have surfactant dysfunction and genetic testing was performed before diagnosis of immunodeficiency, of which the results were negative. With human immunodeficiency virus antibody test or immunologic laboratory testing and/or immune genetic panel, acquired immune deficiency syndrome was confirmed in one case, hyper-IgM syndrome was confirmed in two cases and hyper-IgE syndrome in one case, Wiskott-Aldrich syndrome in one and STAT3 gain of function genetic mutation in another. All cases had clinical clues indicative of underlying immunocompromise. Conclusions: The clinical features of immunodeficiency diseases with ILD are cough, tachypnea or hypoxia, respiratory failure with infection, diffuse ground glass opacity in Chest CT imaging. With thorough medical history and immunology screening, there would be clinical clues indicative of underlying immunocompromise. Screening for immunodeficiency disease should be emphasized in the differential diagnosis of ILD, otherwise it may lead to misdiagnosis or unnecessary testing.

Hyper IgE syndrome associated with novel DOCK8 heterozygous mutation: а case report

Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive combined immunodeficiency within the spectrum of hyper-IgE syndromes.Here we report a patient with a novel heterozygous mutation in DOCK8 gene associated with a clinical presentation of hyper-IgE syndrome (HIES).A case report. The patient presented with severe congenital atopic dermatitis, allergic rhinitis and bronchial asthma which was developed during the 3rd year of life. Also, the patient suffered from recurrent otitis and lymphadenopathy of the inguinal lymph nodes. The immune evaluation showed normal lymphocytes subpopulation and increased serum IgE — 32.131 ІU/L. Genetic sequencing revealed a heterozygous defect c.5266A>T (p.Ile1756Phe) in the DOCK8 gene. Therapy with omalizumab was started and a significant improvement of skin syndrome was achieved.Conclusions. Our data and therapeutic approach may be clinically useful as the diagnostic and treatment approach for severe atopic dermatitis that does not fit the full criteria for previously reported hyper-IgE syndromes.The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institution. The informed consent of the child's parents was obtained from the studies.No conflict of interest was declared by the authors.

Loiasis in sub-Saharan migrants living in Spain with emphasis of cases from Equatorial Guinea

BackgroundLoiasis is an uncommon and poorly understood parasitic disease outside endemic areas of Africa. The aim of this study was to describe the clinical and biological patterns and treatment of imported loiasis by sub-Saharan migrants diagnosed in Madrid, Spain.MethodsA retrospective study was conducted with sub-Saharan immigrants seen at the Tropical Medicine Unit of the Carlos III Hospital in Madrid, Spain, a reference center, over 19 years. Categorical variables were expressed as frequency counts and percentages. Continuous variables were expressed as the mean and standard deviation (SD) or median and interquartile range (IQR: Q3–Q1). Chi-square tests were used to assess the association between categorical variables. The measured outcomes were expressed as the odds ratio (OR) with a 95% confidential interval. Continuous variables were compared by Student’s t-tests or Mann-Whitney U tests. Binary logistic regression models were used. P < 0.05 was considered a statistically significant difference.ResultsOne hundred thirty-one migrants from tropical and subtropical areas with loiasis were identified. Forty-nine patients were male (37.4%). The migrants’ mean age (±SD) was 42.3 ± 17.3 years, and 124 (94.7%) were from Equatorial Guinea. The median time (IQR) between arrival in Spain and the first consultation was 2 (1–7) months. One hundred fifteen migrants had eosinophilia, and one hundred thirteen had hyper-IgE syndrome. Fifty-seven patients had pruritus (43.5%), and thirty patients had Calabar swelling (22.9%). Seventy-three patients had coinfections with other filarial nematodes (54.2%), and 58 migrants had only Loa loa infections (45.8%). One hundred two patients (77.9%) were treated; 45.1% (46/102) patients were treated with one drug, and 54.9% (56/102) patients were treated with combined therapy. Adverse reactions were described in 14 (10.7%) migrants.ConclusionsOur patients presented early clinical manifestations and few atypical features. Thus, physicians should systematically consider loiasis in migrants with a typical presentation. However, considering that 72.5% of the patients had only positive microfilaremia without any symptoms, we suggest searching for microfilaremia in every migrant from endemic countries for loiasis presenting with eosinophilia.

Primary Immunodeficiency Diagnoses seen in Patients with Chronic Lung Disease: Findings from the USIDNET Registry

In patients with chronic lung disease (CLD), a diagnosis of underlying primary immunodeficiency (PID) can have unique implications on evaluation and management. It is important to recognize the full spectrum of PID diagnoses that can present with CLD. The USIDNET Registry was queried for patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Demographics, diagnoses, diagnosis dates, infections, immunology tests, and treatments were extracted. There were 116 patients (median age 22 years, range 0-81) with reported ILD (90.5%, 105/116) and COPD (20.7%, 24/116). Both ILD and COPD were reported in 11.2% (13/116). PIDs most commonly reported with ILD were common variable immunodeficiency (CVID) (56.2%, 59/105), severe combined immunodeficiency (11.4%, 12/105), and chronic granulomatous disease (CGD) (7.6%, 8/105). Chronic mucocutaneous candidiasis (CMC), Hyper-IgE Syndrome (HIES), and PIK3CD disorder were reported in 2.9% (3/105); autoimmune lymphoproliferative syndrome, GATA2 deficiency, hypogammaglobulinemia, IL-10 mutation, X-linked agammaglobulinemia in 1.9% (2/105); and ataxia-telangiectasia, CTLA4 deficiency, DiGeorge Syndrome, Hyper-IgM syndrome in 1.0% (1/105). ILD diagnosis preceded or coincided with PID diagnosis in 29.5% (31/105). PIDs commonly reported with COPD were CVID (37.5%, 9/24), HIES (16.7%, 4/24), and PIK3CD disorder (8.3%, 2/24). CGD, CMC, combined immunodeficiency, GATA2 deficiency, and hypogammaglobulinemia were reported in 4.2% (1/24). COPD diagnosis preceded or coincided with PID diagnosis in 25.0% (6/24). CLD was associated with a range of PID diagnoses. Importantly, PID was diagnosed after or at time of CLD diagnosis in 29.3% (34/116) of patients, providing support that immune evaluation may be prudent in CLD patients with frequent infections.

Hyper IgE syndromes: clinical and molecular characteristics

Hyper IgE syndromes(HIES)comprise a group of rare primary immunodeficiency disorders characterized by a triad of atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels.According to clinical and molecular characteristics, HIES can be classified into 2 types: autosomal dominant HIES(AD-HIES)and autosomal recessive HIES(AR-HIES). At present, STAT3, DOCK8, IL6ST and ZNF341 are included in OMIM database.AD-HIES, caused by STAT3 mutations, can present multiple systemic clinical symptoms and even lead to the development of pulmonary structural abnormalities including pneumatoceles and bronchiectasis.AR-HIES, caused by DOCK8, IL6ST or ZNF341 mutations, often present with severe fungal, bacterial or viral infections.Neurologic manifestations are frequent complications, such as vasculitis, hemangioma and cerebral infarction.The mortality rate is high.There is no specific index for the clinical diagnosis of HIES, and the final diagnosis still needs to be combined with genetic diagnosis.This article reviews the above genes and their possible pathogenesis. Key words: Hyper IgE syndromes; STAT3; DOCK8; IL6ST; ZNF341

Does Allergy Break Bones? Osteoporosis and Its Connection to Allergy.

Osteoporosis and allergic diseases are important causes of morbidity, and traditionally their coexistence has been attributed to causality, to independent processes, and they were considered unrelated. However, the increasing knowledge in the field of osteoimmunology and an increasing number of epidemiological and biological studies have provided support to a correlation between bone and allergy that share pathways, cells, cytokines and mediators. If the link between allergic pathology and bone alterations appears more subtle, there are conditions such as mastocytosis and hypereosinophilic or hyper-IgE syndromes characterized by the proliferation of cells or hyper-production of molecules that play a key role in allergies, in which this link is at least clinically more evident, and the diseases are accompanied by frank skeletal involvement, offering multiple speculation cues. The pathophysiological connection of allergy and osteoporosis is currently an intriguing area of research. The aim of this review is to summarize and bring together the current knowledge and pursue an opportunity to stimulate further investigation.

Factors causing oral and skin pathological features in the hyperimmunoglobulin E syndrome patient including the environmental component: a review of the literature and own experience.

The hyperimmunoglobulin E syndrome (HIES) is a rare multi-system disease with non-immunological as well as immunological abnormalities. The syndrome is characterized by a triad of the most distinctive symptoms, such as pneumonia with pneumatocele formation, recurring staphylococcal skin abscesses and a high serum concentration of IgE. Central mediators of immune responses such as STAT1 and STAT3 affect immune responses and contribute to changes of the skin microbiome which subsequently can amplify the defective immune response against microbial and fungal pathogens. Reactions related to an environmental factor, such as sun-induced skin changes, in individuals during long-term medication therapy have also been reported. The dermatological symptoms, oral status and other health problems of a hyperimmunoglobulin E syndrome paediatric patient are presented. HIES is of great importance to different professionals because sufferers require special preventive and therapeutic management from early infancy in order to avoid complications which can even prove to be life-saving for such patients.

STAT3 modulates reprogramming efficiency of human somatic cells; insights from autosomal dominant Hyper IgE syndrome caused by STAT3 mutations.

ABSTRACTHuman induced pluripotent stem cell (iPSC) technology has opened exciting opportunities for stem-cell-based therapy. However, its wide adoption is precluded by several challenges including low reprogramming efficiency and potential for malignant transformation. Better understanding of the molecular mechanisms of the changes that cells undergo during reprograming is needed to improve iPSCs generation efficiency and to increase confidence for their clinical use safety. Here, we find that dominant negative mutations in STAT3 in patients with autosomal-dominant hyper IgE (Job's) syndrome (AD-HIES) result in greatly reduced reprograming efficiency of primary skin fibroblasts derived from skin biopsies. Analysis of normal skin fibroblasts revealed upregulation and phosphorylation of endogenous signal transducer and activator of transcription 3 (STAT3) and its binding to the NANOG promoter following transduction with OKSM factors. This coincided with upregulation of NANOG and appearance of cells expressing pluripotency markers. Upregulation of NANOG and number of pluripotent cells were greatly reduced throughout the reprograming process of AD-HIES fibroblasts that was restored by over-expression of functional STAT3. NANOGP8, the human-specific NANOG retrogene that is often expressed in human cancers, was also induced during reprogramming, to very low but detectable levels, in a STAT3-dependent manner. Our study revealed the critical role of endogenous STAT3 in facilitating reprogramming of human somatic cells.

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Approach to primary immunodeficiency.

Primary immunodeficiency diseases are inherited defects of the innate or adaptive arms of the immune system that lead to an increase in the incidence, frequency, or severity of infections and/or immune dysregulation. There may be defects in the adaptive arm of the immune system, including combined immunodeficiencies and antibody deficiency syndromes, or abnormalities in innate immunity, such as defects of phagocytes, the complement pathway, or toll-like receptor mediated signaling. Recurrent sinopulmonary infections with encapsulated bacteria such as Haemophilus influenzae type B or Streptococcus pneumoniae may be characteristic of an antibody deficiency syndrome. Frequent viral, fungal, or protozoal infections may suggest T lymphocyte impairment. Multiple Staphylococcus skin infections and fungal infections may imply neutrophil dysfunction or the Hyper-IgE syndrome, and recurrent Neisseria infection is a characteristic manifestation of late complement component (C5-9, or the membrane attack complex) defects. Recurrent viral or pyogenic bacterial infections, often without the presence of a significant inflammatory response, suggest a defect in toll-like receptor signaling. Mycobacterial infections are characteristic of defects in the interleukin (IL) 12/interferon γ pathway. Screening of newborns for T-cell lymphopenia by using polymerase chain reaction to amplify T-cell receptor excision circles, which are formed when a T cell rearranges the variable region of its receptor, serves as a surrogate for newly synthesized naive T cells. Because of very low numbers of T-cell receptor excision circles, severe combined immunodeficiency, 22q11.2 syndrome, and other causes of T-cell lymphopenia have been identified in newborns.

ILC3 deficiency and generalized ILC abnormalities in DOCK8-deficient patients.

Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n=12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

Generation of human induced pluripotent stem cell lines (NIHTVBi011-A, NIHTVBi012-A, NIHTVBi013-A) from autosomal dominant Hyper IgE syndrome (AD-HIES) patients carrying STAT3 mutation.

Autosomal dominant Hyper IgE syndrome (AD-HIES), a rare immune deficiency affecting fewer than one per million people, is caused by heterozygous deleterious mutations in STAT3. STAT3 signaling plays crucial roles in basic cellular functions affecting broad aspects of cellular homeostasis. Accordingly, in addition to immunological deficits, patients experience severe multisystem non-immunological features. Human induced pluripotent stem cells (hiPSC) are well established as in vivo disease models for various human pathologies. We describe the generation of iPSC from three AD-HIES patients. These iPSCs express pluripotency markers, differentiate into three germ layers, have normal karyotype and similar genome identity to parental cells.

Systemic anaplastic large cell lymphoma presenting as a huge mediastinal mass in a case of hyper IgE syndrome: a case report

BackgroundHyper IgE syndrome is a rare heterogeneous immunodeficiency syndrome which is characterized by recurrent episodes of cutaneous and respiratory tract infections and development of cold abscesses. This syndrome is also associated with malignancies, most notability hematologic malignancies.Case presentationIn this case report, we discuss a 27-year-old male with proven hyper IgE syndrome and effected by tuberculosis, who developed an anaplastic large cell lymphoma, a very rare and aggressive subtype of lymphoma. We will discuss imaging findings in this rare case. The case presented here had a large mediastinal mass, which had encircled the aorta, and was accompanied by subcarinal lymphadenopathy and inguinal lymphadenopathy.ConclusionsSystemic anaplastic large cell lymphoma is a rare subtype of lymphoma which is rarely associated with hyper IgE syndrome. In this case, both lymphoma and tuberculosis infection were witnessed in the same patient, showing a classic example of immune dysregulation.