An update on signal transduction and activator of transcription 3-hyper-IgE syndrome / 中华实用儿科临床杂志

Hyper-IgE syndrome (HIES) comprises a group of rare primary immunodeficiencies, which are characterized by extremely high serum IgE levels, eczema, recurrent skin and pulmonary infections.Signal transduction and activator of transcription 3( STAT3)-HIES is the most common type, which is caused by dominant-negative mutations in STAT3.STAT3-HIES confers broad innate and acquired immune defects, defects in skeletal, connective tissue, and vascular functions, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infections, scoliosis and minimal trauma fractures, vascular tortuosity and aneurysm.In this article, the advance in diverse clinical manifestations and management strategies of STAT3-HIES was summarized.

Advances of Dupilumab in Treating Rare Monogenic Inherited Skin Diseases / 罕见病研究

Monogenic inherited skin diseases are a group of clinically rare diseases that include nearly 1000 phenotypically distinct disorders. Through the concerted efforts of researchers in dermatological sciences and related disciplines worldwide, many advances have been made in the etiology and pathogenesis of these diseases in the last 30 years. However, it is important to note that the treatment of the majority of monogenic inherited skin diseases remains a challenge for clinicians. Dupilumab is a fully human monoclonal IgG4 antibody that specifically binds to the α subunit of the IL-4 receptor, thereby inhibiting the IL-4 and IL-13 signaling pathway. It was first approved for the treatment of moderate-to-severe atopic dermatitis (AD) and has been used worldwide. In recent years, the drug has been successfully used to treat some monogenic inherited skin diseases with AD-like clinical manifestations, such as hyper-IgE syndrome and Netherton syndrome, with good efficacy. The drug was later tried for the treatment of other monogenic inherited skin diseases, such as Hailey-Hailey syndrome and epidermolysis bullosa pruriginosa, where it was also proven to be effective. In this paper, we review literature reports related to dupilumab for the treatment of monogenic inherited skin diseases in recent years, focusing on its efficacy, safety and possible therapeutic mechanisms. We aim to provide a possible scientific basis for the future application of this drug in the field of rare monogenic inherited skin diseases.

Research progress of primary immunodeficiency disease with hyper IgE syndrome / 中华实用儿科临床杂志

The hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels.The JOB syndrome due to heterozygous loss-of-function mutations in the signal transduction and transcription activator-3(STAT3) gene is the prototype of HIES.However, several other immunodeficiency disorders with the phenotype of HIES have been identified over the past decade.This study aims to review these disorders and their molecular mechanisms, aiming to improve the understanding of this rare disease.

Clinical and genetic characteristics and differential diagnosis in children with autosomal dominant hyper-IgE syndrome / 中华实用儿科临床杂志

Objective:To summarize the clinical features of children with autosomal dominant hyper-IgE syndrome (AD-HIES) and the differential diagnosis of hyper-IgE syndrome and allergic diseases as well.Methods:All clinical data, including general information, clinical features, and genetic changes, from 7 children with AD-HIES who were diagnosed in Beijing Children′s Hospital Affiliated to Capital Medical University from April 2016 to June 2020 were analyzed retrospectively.The diagnostic criteria are based on the National Institutes of Health′s (NIH)′s hyper-IgE syndrome score and combined with the results of gene detection, shown as follows: (1) NIH score over 40, with signal transducer and activator of transcription 3 gene ( STAT3) pathogenic mutation; (2) NIH score between 20 and 40, with reported STAT3 pathogenic mutation; (3) NIH score less than 20 points was excluded. Results:There were 3 males and 4 females.The onset age of 7 cases was within 2 months after birth, and the mean age at diagnosis was 3 years old.All seven cases had recurrent skin or lung infections, with 4 cases having skin and lung infections, 1 case of skin abscesses at the BCG vaccination site, and 2 cases without skin infection suffering from recurrent pneumonia.The mean onset age of skin abscess in 5 cases was 1.5 years, and pus culture of 3 cases were Staphylococcus aureus.Four cases developed bullae and 6 cases had lung infections.Four cases had otitis media, and oral thrush was seen in 4 cases.One case of skin and lung infection developed liver abscess and sepsis.Seven cases had eczema, which was disco-vered in the neonatal period for 6 cases.Four cases had the symptoms of eczema for the first visit.Two cases had food allergy, and 1 case had recurrent wheezing within 1 year old.The serum IgE level and blood eosinophil count in 7 children were elevated.All children had heterozygous pathogenic mutations in STAT3.Six patients had de novo mutations.There were 6 different mutation sites.The 4 mutation sites were reported: c.1145G>A, c.1144C>T, and c. 1699A>G were missense mutations, and c. 1139+ 5G>A was splicing mutation.Two mutation sites had not been reported: c.1031A>C was missense mutation, and c. 2050G>T was nonsense mutation.The pathogenic grade of them were likely pathogenic, and the NIH score of 2 cases were above 40 score, which was consistent with the clinical diagnosis of hyper-IgE syndrome. Conclusions:Eczema is a common and early clinical manifestation of hyper-IgE syndrome, along with elevated IgE levels and eosinophil counts that need to be differentiated from allergic diseases.On the contrary, it often had recurrent skin abscesses or pneumonia, which was prone to bullae.The clinical manifestations of young children were atypical, and genetic testing was helpful for early diagnosis.

Toll-like receptors in B cell activation and STAT3 signal pathway / 国际儿科学杂志

Toll-like receptors(TLR) are widely exist in antigen presenting cells as a kind of pattem 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.

Functional Defects in Type 3 Innate Lymphoid Cells and Classical Monocytes in a Patient with Hyper-IgE Syndrome

Hyper-IgE syndrome (HIES) is a very rare primary immune deficiency characterized by elevated serum IgE levels, recurrent bacterial infections, chronic dermatitis, and connective tissue abnormalities. Autosomal dominant (AD) HIES involves a mutation in signal transducer and activator of transcription 3 (STAT3) that leads to an impaired T(H)17 response. STAT3 signaling is also involved in the function of RORγt⁺ type 3 innate lymphoid cells (ILC3s) and RORγt⁺T(H)17 cells. The aim of this study was to investigate the role of innate immune cells such as innate lymphoid cells (ILCs), granulocytes, and monocytes in a patient with HIES. Peripheral blood mononuclear cells (PBMCs) from a patient with HIES and three age-matched healthy controls were obtained for the analysis of the innate and adaptive immune cells. The frequencies of ILCs in PBMCs were lower in the patient with HIES than in the controls. Moreover, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17A produced by ILC3s in PBMCs were lower in the patient with HIES than the controls. Compared with the controls, classical monocytes (CD14⁺CD16(low)), which have a high antimicrobial capability, were also lower in the patient with HIES, while non-classical monocytes (CD14(low)CD16⁺) as well as intermediate monocytes (CD14⁺CD16(intermediate)) were higher. Taken together, these results indicate that the impaired immune defense against pathogenic microbes in the patient with HIES might be partially explained by functional defects in ILC3s and inflammatory monocytes.

Síndrome de hiper IgE autosómico dominante / Autosomal dominant hyper IgE síndrome

El síndrome hiper IgE autosómico dominante es una inmunodeficiencia primaria poco frecuente que se caracteriza por niveles elevados de IgE, dermatitis eccematoide, infecciones recurrentes de piel y pulmón, y formación de abscesos con escasos signos inflamatorios. También se presentan alteraciones dentarias, esqueléticas y del tejido conjuntivo. Es causado por mutaciones dominantes del gen que codifica la proteína transductora de señal y activadora de la transcripción 3 (STAT3). Esta mutación condiciona un déficit en la generación de células Th17 a partir de células T CD4+, que explica la susceptibilidad de estos pacientes a infecciones por S aureus y C albi cans. Se presenta una adolescente con puente nasal amplio, paladar ojival, hiperlaxitud, fracturas patológicas, escoliosis y retraso en la caída de la dentadura primaria, rash eccematoso desde el período neonatal, infecciones cutáneas, óticas, pulmonares y candidiasis mucocutánea. Se detectan niveles elevados de IgE sérica y eosinofilia. Ha sido tratada con antimicrobianos y tópicos, con seguimiento de más de 10 años. Este síndrome es una entidad infrecuente, de causa genética, que requiere alto grado de sospecha y del manejo precoz de las infecciones.

Autosomal dominant hyper IgE syndrome is a rare primary immunodeficiency characterized by elevated levels of IgE, eczematoid dermatitis, recurrent infections of skin and lung and abscess formation with few inflammatory signs. Dental, skeletal and connective tissue disorders are also present. It is caused by dominant mutations of the gene encoding the protein signal transducer and activator of transcription 3 (STAT3) . This mutation deficit conditions in generating Th17 cells from CD4 + T cells which explains the special susceptibility of these patients to infection by S. aureus and Candida albicans. A teenager patient is presented, broad nasal bridge, arched palate, hypermobility, pathological fractures, scoliosis and fall of primary teeth delayed, eczematous rash from neonatal lung, skin infections, ear and mucocutáneous candidiasis. High levels of Ig E serum and eosinophilia were detected. The patient was treated with antibiotics and topical, tracking over 10 years. Conclusions: This syndrome is a rare condition, genetic causes require high degree of suspicion and early management of infections.

Síndrome de hiper IgE, una enfermedad poco frecuente en edad adulta: Reporte de un caso / Hyper-immunoglobulin E syndrome: Report of one case

The Hyperimmunoglobulin E syndrome (HIES) is a rare sporadic or autosomal dominant immune and connective tissue disorder characterized by chronic eczema, cutaneous abscesses, pneumonias, invasive infections, high levels of Immunoglobulin E, primary teeth retention and bone abnormalities. We report a 24-year-old male with a history of cutaneous abscesses and esophageal candidiasis. He was admitted due to a left gluteal cellulitis. During the fifth day of hospitalization he presented a distal necrosis of the fourth finger of the right hand. Laboratory results showed high levels of IgE and positive cryoglobulins. The patient was discharged and was admitted again five days later with a new gluteal abscess. IgE levels were even higher. Applying Grimbacher scale, the diagnosis of Hyperimmunoglobulin E syndrome was reached.

Clinical manifestations of different types of gene mutations in hyper-IgE syndrome / 国际儿科学杂志

Hyper-IgE syndrome (HIES)is a complex primary immunodeficiency characterized by extremely high serum IgE levels, while presented a normal level of other immunoglobulins (IgG, IgA and IgM).Recent studies demonstrated that gene mutations, namely STAT3,Tyk2 or DOCK8 gene mutations, are the main mechanism of HIES.The clinical manifestations in HIES are significantly different in patients with different gene mutation.Therefore, investigation of the clinical manifestations caused by various gene mutations is very important, because it is beneficial not only for the clinical diagnosis and therapeutic evaluation, but also for scientific research.

Síndrome de Job asociado a tuberculosis miliar

El síndrome de hiper IgE también denominado síndrome de Job, es una inmunodeficiencia primaria poco frecuente, cuyo modo de herencia puede ser autosómico recesivo o dominante. Se caracteriza por altos niveles de IgE, eosinofilia, abscesos cutáneos, eccema, candidiasis mucocutánea crónica e infecciones pulmonares recidivantes que contribuyen al desarrollo de neumatoceles y bronquiectasias. El germen más frecuentemente aislado es el Staphylococcus aureus. En la actualidad, ante la mayor supervivencia de los pacientes se han comunicado infecciones oportunistas y linfomas. Existen escasas publicaciones de pacientes con enfermedad por Mycobacterium tuberculosis asociada a síndrome de hiper IgE, por lo que consideramos relevante comunicar el caso de un paciente con antecedentes de una tuberculosis pulmonar, que presentó una tuberculosis miliar con grave compromiso respiratorio, con buena respuesta al tratamiento estándar con drogas de primera línea.

The hyper Immunoglobulin E syndrome, also known as Job´s syndrome, is a rare primary immunodeficiency, its mechanisms of inheritance maybe recessive or dominant autosomal. It is characterized by high levels of IgE, eosinophilia, skin abscesses, eczema, chronic mucocutaneous candidiasis and recurrent pulmonary infections all of which contribute to the development of pneumatoceles and bronchiectasis. The most frequently isolated bacteria is Staphylococcus aureus. Currently, despite the highest survival of patients, lymphomas and other opportunistic infections have been reported. There are few reports of patients with Mycobacterium tuberculosis infection associated with hyper IgE syndrome. Therefore it is relevant that we report a case history of a patient with pulmonary tuberculosis, presenting miliary tuberculosis and severe respiratory compromise, who responded positively to standard anti-tuberculous treatment with first line drugs.

Síndrome hiper IGE: a propósito de tres casos clínicos / Hyper IGE syndrome: three case reports

Introducción: El síndrome Hiper IgE (SHIGE) autosómico dominante (SHIGE-AD) es una inmunodeficiencia primaria asociada a alteraciones del tejido conectivo, esqueléticas, cerebrales y vasculares. La patogénesis de la inmunodeficiencia reside en una alteración en la vía Th17 lo que explica la susceptibilidad especial de estos pacientes a infecciones por S. aureus y Candida. Objetivo: Describir tres niños diagnosticados como síndrome Hiper IgE y realizar una revisión sobre el tema, con especial foco en la forma dominante de la enfermedad. Casos clínicos: Se presentan 3 niños con SHIGE (2 varones), con rash eccematoso desde el período de recién nacido, infecciones cutáneas, óticas, pulmonares, ganglionares, con niveles de IgE sérica sobre 2.000 UI/ml y eosinofilia, tratados con antimicrobianos y tópicos, con seguimiento más de 7 años. Conclusiones: Es una entidad infrecuente, que requiere alto grado de sospecha y el manejo precoz de las infecciones. Uno de sus principales diagnósticos diferenciales está dado por el niño atópico con infecciones recurrentes pero difieren en el contexto, respuesta y resolución frente a las infecciones y la falta de las otras características fenotípicas.

Introduction: Autosomal dominant Hyper IgE syndrome (HIES-AD) is a primary immunodeficiency associated with connective tissue, skeletal, vascular and brain disorders. The pathogenesis of immune deficiency lies in an alteration of Th17 cells which explains the special susceptibility of these patients to S. aureus and Candida infections. Objective: To describe three children diagnosed with hyper IgE syndrome and conduct a study on the subject, with special focus on the dominant form of the disease. Case reports: 3 children with HIES-AD (2 males and one female) with eczema since birth, skin, ear, lung, and lymph node infections, and serum IgE levels over 2,000 IU/ml and eosinophilia values, treated with antibiotics and topically, and 7 year follow-up. Conclusions: It is a rare condition that requires a high index of suspicion and early management of infections. One of its main diagnoses is atopic syndrome with recurrent infections but both conditions differ in context, response and resolution against infections and lack of other phenotypic characteristics.

STAT3 mutations correlated with hyper-IgE syndrome lead to blockage of IL-6/STAT3 signalling pathway.

Of all the causes identified for the disease hyper-immunoglobulinemia E syndrome (HIES), a homozygous mutation in tyrosine kinase2 (TYK2) and heterozygous mutations in STAT3 are implicated the defects in Jak/STAT signalling pathway in the pathogenesis of HIES. Mutations of STAT3 have been frequently clinically identified in autosomaldominant (AD) HIES patients’ cells, and therefore, the genotype of STAT3 has been associated with the phenotype of HIES. Here, we conducted studies on the functional loss of the seven specific STAT3 mutations correlated with ADHIES. Using STAT3-null human colon carcinoma cell line A4 cells, we generated seven mutants of STAT3 bearing single mutations clinically identified in AD-HIES patients’ cells and studied the functional loss of these mutants in IL- 6-Jak/STAT3 signalling pathway. Our results show that five STAT3 mutants bearing mutations in the DNA-binding domain maintain the phosphorylation of Tyr705 and the ability of dimerization while the other two with mutations in SH2 domain are devoid of the phosphorylation of Try705 and abrogate the dimerization in response to IL-6. The phosphorylation of Ser727 in these mutants shows diversity in response to IL-6. These mutations eventually converge on the abnormalities of the IL-6/Gp130/Jak2-mediated STAT3 transactivation on target genes, indicative of the dysregulation of JAK/STAT signalling present in HIES.

A case of Hyper-IgE syndrome with a mutation of the STAT3 gene / 소아과

Hyperimmunoglobulin E syndrome (HIES) is a rare immunodeficiency disease which is characterized by high serum IgE levels, eczema, and recurrent infections. Herein we present the case of a patient with HIES associated with STAT3 gene (stat3) mutation. A 16 year-old girl was admitted to our hospital due to hemoptysis caused by pneumonia with bronchiectasis. She had a history of recurrent skin and respiratory tract infections, such as pneumonia caused by MRSA (methicillin-resistant Staphylococcus aureus) and Pseudomonas aeruginosa. On physical examination, a broad round shaped nose, oral thrush, and chronic eczematous skin rash over her whole body were found. Laboratory data showed an elevated eosinophil count (750/microliter) and total IgE level (5,001 U/mL). The patient's National Institutes of Health (NIH) score for HIES was 44. Direct sequencing of the STAT3 gene revealed that the patient was heterozygous for a missense mutation in the DNA binding domain of the STAT3 protein (c.1144C>T, p. Arg382Trp). HIES should be suspected in patients with recurrent infections and can be confirmed by clinical scoring and genetic analysis.

A Case of Hyper-IgE Syndrome Presenting as a Vesiculopustular Eruption in an Infant / 대한피부과학회지

The hyper-IgE syndrome is characterized by marked elevated levels of IgE, recurrent cutaneous and systemic staphylococcal infections, peripheral eosinophilia and defective neutrophil chemotaxis. The characteristic cutaneous findings of hyper-IgE syndrome have been reported as an eczematous or atopic dermatitis-like eruption with multiple skin abscesses, whereas the initial presentation of hyper-IgE syndrome in infancy as a papulopustular or vesicular eruption. We report a case of hyper-IgE syndrome featuring a vesiculopustular eruption in infancy. A 15-month-old baby presented with recurrent vesiculopustules on the face and hands. The biopsy specimen revealed eosinophilic spongiotic dermatitis with an eosinophil-predominant perivascular lymphocytic infiltration. These findings might lead to an earlier recognition of hyper-IgE syndrome and an institution of appropriate treatment.