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1.
BMC Med Genet ; 20(1): 114, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242861

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency (MIM #243700) is a rare disease, leads to a combined primary immunodeficiency (PID), and accounts for the autosomal recessive-hyper immunoglobulin E syndrome (AR-HIES). DOCK8 deficiency status characterizes by recurrent infections, atopy, and risk of cancer. Lymphoproliferative disease complicating PID, is difficult to diagnose. Our aim is to present a rare case of PID, and to the best of our knowledge, she is the first case of DOCK8 deficiency from Iraq. The genetic diagnosis was carried out in Japan using dried blood spot-based DNA transfer and whole-exome sequencing. CASE PRESENTATION: An 11-year-old Iraqi girl, of double first-cousin-parents, had a history of severe eczema, food allergy, and repeated infections. She presented with a jaw mass, bilateral cervical and axillary lymphadenopathy, and immunoglobulin (Ig) assays of 20, 3.3 and 1.7-fold above maximum normal level for age of IgE, IgA and IgG, respectively, along with a low IgM, eosinophilia and lymphopenia. Based on the jaw mass biopsy, non-Hodgkin lymphoma was suggested in Iraq, whereas histopathological re-evaluation in Japan revealed the diagnosis of a polyclonal reactive proliferation spectrum of lymphoproliferative disorders/plasmacytic hyperplasia, complicating PID. Whole-exome sequencing supported the diagnosis of PID by identifying a homozygous DOCK8 mutation with previously reported pathogenicity (NM_203447:c.3332delT, p.Phe1113Leufs*2), that may be attributed to consanguinity. CONCLUSIONS: International collaboration using an effective DNA transportation technique and next-generation sequencing was the key to pinpoint the diagnosis of DOCK8 deficiency. Our case asserted that careful pathogenetic evaluation, in an advanced setting, was crucial for ruling out the neoplastic process. Pediatricians in areas with a high prevalence of consanguinity marriage should have a high index of suspicion of DOCK8 deficiency in patients with recalcitrant eczema, and frequent respiratory and skin infectious episodes.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/genética , Mutação , Sequenciamento Completo do Exoma/métodos , Anticorpos/sangue , Criança , Consanguinidade , DNA/sangue , Eosinofilia/imunologia , Feminino , Homozigoto , Humanos , Iraque , Japão , Arcada Osseodentária/patologia , Síndrome de Job/diagnóstico por imagem , Síndrome de Job/imunologia , Síndrome de Job/patologia , Linfopenia/imunologia , Transtornos Linfoproliferativos/genética , Linhagem
2.
Allergol. immunopatol ; 47(2): 152-158, mar.-abr. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-180803

RESUMO

Introduction and objectives: Long-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 patients: In 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. Results: Eighteen 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. Conclusions; AD-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


No disponible


Assuntos
Humanos , Masculino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Hipersensibilidade Alimentar/imunologia , Síndrome de Job/imunologia , Mutação/genética , Pneumonia/imunologia , Seguimentos , Hipersensibilidade Alimentar/genética , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/genética , Fenótipo , Pneumonia/genética , Fator de Transcrição STAT3/genética
4.
Immunol Cell Biol ; 97(4): 368-379, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30264496

RESUMO

Hyper IgE syndromes 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. Job syndrome or autosomal dominant hyper IgE syndrome because of heterozygous loss-of-function mutations with dominant negative effect in signal transducer and activator of transcription-3 is the prototype of these disorders. However, several other genetically characterized immunodeficiency disorders have been identified over the past decade and joined the umbrella of hyper IgE syndromes including autosomal recessive mutations in the DOCK8, ZNF431 and PGM3 genes and heterozygous mutations with dominant negative effect in the CARD11 gene. Moreover, a number of phenotypically distinct immunodeficiency disorders can mimic hyper IgE syndromes, adding to the diagnostic challenge. Herein, we will concisely review these disorders, their molecular bases, highlighting key distinguishing clinical and laboratory findings and therapeutic options.


Assuntos
Síndrome de Job/genética , Genes Dominantes , Humanos , Síndrome de Job/diagnóstico , Síndrome de Job/imunologia , Síndrome de Job/terapia , Mutação/genética , Fenótipo , Fator de Transcrição STAT3/genética , Transcrição Genética
5.
Allergol Immunopathol (Madr) ; 47(2): 152-158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30279075

RESUMO

INTRODUCTION AND OBJECTIVES: Long-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 PATIENTS: In 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. RESULTS: Eighteen 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. CONCLUSIONS: AD-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.


Assuntos
Hipersensibilidade Alimentar/imunologia , Síndrome de Job/imunologia , Pneumonia/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Seguimentos , Hipersensibilidade Alimentar/genética , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Irã (Geográfico) , Síndrome de Job/genética , Masculino , Mutação/genética , Fenótipo , Pneumonia/genética , Fator de Transcrição STAT3/genética , Adulto Jovem
6.
Eur J Immunol ; 48(12): 1975-1988, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315710

RESUMO

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.


Assuntos
Eosinofilia/imunologia , Eosinófilos/imunologia , Síndrome de Job/imunologia , Neutrófilos/imunologia , Fator de Transcrição STAT3/metabolismo , Adolescente , Adulto , Morte Celular , Células Cultivadas , Criança , Pré-Escolar , Transtornos Cromossômicos , Estudos de Coortes , Feminino , Humanos , Masculino , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Adulto Jovem
7.
JCI Insight ; 3(17)2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30185668

RESUMO

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.


Assuntos
Disbiose , Síndrome de Job/imunologia , Microbiota/imunologia , Mucosa Bucal/microbiologia , Fator de Transcrição STAT3/metabolismo , Adulto , Candida albicans , Candidíase , Cárie Dentária/microbiologia , Feminino , Humanos , Interleucina-17 , Síndrome de Job/genética , Masculino , Microbiota/genética , Pessoa de Meia-Idade , Mutação , RNA Ribossômico 16S , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Streptococcus mutans , Streptococcus oralis , Células Th17 , Adulto Jovem
8.
Curr Opin Allergy Clin Immunol ; 18(6): 445-452, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30188342

RESUMO

PURPOSE OF REVIEW: Understanding the pathophysiology of monogenic primary immunodeficiency (PID) with atopic presentation has pivotal implications for intervention strategies and potentially wider polygenic atopic-related traits. This review will discuss advances in gene discovery arising from monogenic defects at the interface between PID and atopy, notably the hyper-IgE syndromes. RECENT FINDINGS: Key molecular pathways underlying development of primary atopic diseases have recently been proposed. We test this classification through reviewing novel genes reported in the last 2 years and compare insights from pathway-analysis of genome-wide association studies (GWAS) of atopic-related traits.Growing access to next-generation sequencing (NGS) has resulted in a surge in gene discovery, highlighting the utility and some pitfalls of this approach in clinical practice. The variability of presenting phenotypes reveals important gene-dosage effects. This has important implications for therapeutic strategies such as protein stabilization and modulators of JAK-STAT or TH2-cytokine signalling. We also consider the therapeutic implications raised by CARD11 deficiency, and wider applications of NGS including polygenic risk score in atopy. SUMMARY: Disorders presenting at the interface between PID and allergy are often difficult to diagnose, with serious consequences if missed. Application of NGS has already provided critical insights to pathways enabling targeted therapeutic interventions, and potential wider translation to polygenic disorders.


Assuntos
Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Hipersensibilidade Imediata , Síndrome de Job , Humanos , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Síndrome de Job/genética , Síndrome de Job/imunologia
10.
J Clin Invest ; 128(8): 3595-3604, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30035749

RESUMO

Autosomal dominant hyper IgE syndrome (AD-HIES), or Job's syndrome, is a primary immune deficiency caused by dominant-negative mutations in STAT3. Recurrent Staphylococcus aureus skin abscesses are a defining feature of this syndrome. A widely held hypothesis that defects in peripheral Th17 differentiation confer this susceptibility has never been directly evaluated. To assess the cutaneous immune response in AD-HIES, we induced suction blisters in healthy volunteers (HVs) and patients with AD-HIES and then challenged the wound with lethally irradiated bacteria. We show that cutaneous production of IL-17A and IL-17F was normal in patients with AD-HIES. Overproduction of TNF-α differentiated the responses in AD-HIES from HVs. This was associated with reduced IL-10 family signaling in blister-infiltrating cells and defective epithelial cell function. Mouse models of AD-HIES recapitulated these aberrant epithelial responses to S. aureus and involved defective epithelial-to-mesenchymal transition (EMT) rather than a failure of bacterial killing. Defective responses in mouse models of AD-HIES and primary keratinocyte cultures from patients with AD-HIES could be reversed by TNF-α blockade and by drugs with reported modulatory effects on EMT. Our results identify these as potential therapeutic approaches in patients with AD-HIES suffering S. aureus infections.


Assuntos
Células Epiteliais/imunologia , Furunculose/imunologia , Síndrome de Job/imunologia , Queratinócitos/imunologia , Staphylococcus aureus/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Animais , Modelos Animais de Doenças , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Furunculose/genética , Furunculose/patologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Síndrome de Job/genética , Síndrome de Job/patologia , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Fator de Necrose Tumoral alfa/genética
11.
Sci Immunol ; 3(24)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907690

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.


Assuntos
Imunocompetência/genética , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Células Th17/imunologia , Fatores de Transcrição/genética , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Núcleo Celular/metabolismo , Criança , Códon sem Sentido , Consanguinidade , Éxons/genética , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lactente , Síndrome de Job/sangue , Síndrome de Job/imunologia , Masculino , Linhagem , Regiões Promotoras Genéticas/genética , Fator de Transcrição STAT3/imunologia , Células Th17/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Adulto Jovem , Dedos de Zinco/genética
12.
Sci Immunol ; 3(24)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

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.


Assuntos
Regulação da Expressão Gênica/imunologia , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Transcrição Genética/imunologia , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Núcleo Celular/metabolismo , Consanguinidade , Citocinas/imunologia , Citocinas/metabolismo , Éxons/genética , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Homozigoto , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Síndrome de Job/sangue , Síndrome de Job/imunologia , Mutação com Perda de Função , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Linhagem , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem , Dedos de Zinco/genética
13.
Front Immunol ; 9: 1080, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868029

RESUMO

Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusion: 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.


Assuntos
Regulação da Expressão Gênica , Síndrome de Job/genética , Mutação com Perda de Função , Osteopontina/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transcrição Genética , Adolescente , Adulto , Sítios de Ligação , Linhagem Celular Tumoral , Pré-Escolar , Biologia Computacional/métodos , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Síndrome de Job/diagnóstico , Síndrome de Job/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Fenótipo , Fosforilação , Estudos Prospectivos , Ligação Proteica , Elementos de Resposta , Proteína 3 Supressora da Sinalização de Citocinas/genética
14.
Medicine (Baltimore) ; 97(14): e0215, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29620631

RESUMO

Hyperimmunoglobulin E syndromes (HIES) are rare primary immunodeficiency diseases characterized by markedly elevated serum immunoglobulin (Ig) E, recurrent pneumonia, and chronic eczema. To date, information about pediatric HIES is limited. We aimed to evaluate the spectrum of clinical and immunological features in pediatric patients with HIES in China.We retrospectively reviewed the cases of 4 pediatric patients with HIES followed at the Guangzhou Women and Children's Medical Center from May 2013 to September 2017. We analyzed clinical presentation, laboratory data, immunological evaluations, imagenological characteristics, treatment, response to therapy, genetic and bronchoalveolar lavage fluid (BALF) findings, and prognosis.The common clinical features of the patients were recurrent respiratory and mucocutaneous infections and eczematoid skin lesions. In 3 of 4 patients, BALF and transbronchial lung biopsy (TBLB) demonstrated fungal pneumonia with organisms including invasive Aspergillus and Penicillium marneffei. Elevated serum IgG and IgM were detected in 3 and 2 cases, respectively, while CD4+ T and CD19+ B cells were slightly reduced in only 1 patient. Nitroblue tetrazolium tests (NBTs) were normal in all patients, and reduced natural killer cell counts were identified in 3 patients. A novel missense mutation in exon 17 (c.1593A>T, p.K531N) was identified in the signal transducer and activator of transcription 3 (STAT3) gene that has not been reported previously. One patient had 3 homozygous nonsynonymous variations of the complement receptor 2 (CR2) gene distributed in exons 10 (c.1916G>A, p.S639N) and 11 (c.1987T>C, p.S663P and c.2012G>A, p.R671H) with high frequency.This case series suggests that fungi are important respiratory pathogens in children with HIES and should be considered in cases of pneumonia in this population. The NIH scoring system does not allow diagnostic certainty, particularly in infants, because some of the common manifestations of HIES may not develop until the patient matures. Pulmonary complications must be identified in the early stage of the disease to treat them effectively. In addition, we report a mutation in STAT3 that has not been identified previously.


Assuntos
Síndrome de Job , Adolescente , Criança , Pré-Escolar , China , Eczema/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/microbiologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Masculino , Pneumonia/imunologia , Pneumonia/microbiologia , Estudos Retrospectivos
15.
Infect Immun ; 86(5)2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29463618

RESUMO

Loss-of-function mutations in the signal transducer and activator of transcription 3 gene (stat3) result in autosomal dominant hyper-IgE syndrome (AD-HIES), a condition in which patients have recurrent debilitating infections, including frequent pneumococcal and staphylococcal pneumonias. stat3 mutations cause defective adaptive TH17 cellular responses, an immune mechanism believed to be critical for clearance of pneumococcal colonization and diminished antibody responses. Here we wished to evaluate the role of stat3 in the clearance of pneumococcal carriage and immunity using mice with a stat3 mutation recapitulating AD-HIES. We show here that naive AD-HIES mice have prolonged nasal carriage of pneumococcus compared to WT mice. Mutant and wild-type mice were then immunized with a pneumococcal whole-cell vaccine (WCV) that provides TH17-mediated protection against pneumococcal colonization and antibody-mediated protection against pneumonia and sepsis. WCV-immunized AD-HIES mice made significantly less pneumococcus-specific interleukin-17A (IL-17A) and antibody than WT mice. The WCV-elicited protection against colonization was abrogated in AD-HIES mice, but immunization with WCV still protected AD-HIES mice against aspiration pneumonia/sepsis. Taken together, our results suggest that impaired clearance of nasopharyngeal carriage due to poor adaptive IL-17A responses may contribute to the increased rates of pneumococcal respiratory infection in AD-HIES patients.


Assuntos
Síndrome de Job/genética , Síndrome de Job/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Células Th17/imunologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Streptococcus pneumoniae/imunologia
16.
J Allergy Clin Immunol Pract ; 6(3): 996-1001, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28939137

RESUMO

BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare condition. OBJECTIVE: Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases. METHODS: A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016. RESULTS: Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P χ2 = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007). DISCUSSION: Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES.


Assuntos
Aspergillus fumigatus/fisiologia , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade Alimentar/epidemiologia , Síndrome de Job/imunologia , Pseudomonas aeruginosa/fisiologia , Sistema de Registros , Infecções Respiratórias/epidemiologia , Pele/patologia , Staphylococcus aureus/fisiologia , Dente/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Eosinofilia , Feminino , Seguimentos , Humanos , Imunoglobulina E/sangue , Síndrome de Job/epidemiologia , Masculino , Anamnese , Pessoa de Meia-Idade , Quebeque/epidemiologia , Adulto Jovem
17.
J Allergy Clin Immunol ; 141(4): 1450-1458, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28916186

RESUMO

BACKGROUND: Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited. OBJECTIVES: This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically. METHODS: Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients. RESULTS: The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome (P < .001), onset of disease at greater than 5 years (P = .02), and absence of multiple affected family members (P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia-telangiectasia mutated (ATM), autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3), and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs. CONCLUSIONS: This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.


Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Adolescente , Criança , Pré-Escolar , Consanguinidade , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Síndromes de Imunodeficiência/mortalidade , Lactente , Irã (Geográfico) , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Masculino , Mutação/genética , Mutação/imunologia , Fenótipo , Estudos Retrospectivos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Análise de Sequência de DNA/métodos , Taxa de Sobrevida
18.
Front Immunol ; 9: 3047, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30671054

RESUMO

The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.


Assuntos
Candidíase Mucocutânea Crônica/metabolismo , Encefalite por Herpes Simples/metabolismo , Influenza Humana/metabolismo , Fatores Reguladores de Interferon/metabolismo , Síndrome de Job/metabolismo , Infecções por Mycobacterium/metabolismo , Fatores de Transcrição STAT/metabolismo , Autoimunidade , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/imunologia , Humanos , Imunidade Inata , Influenza Humana/genética , Influenza Humana/imunologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Janus Quinases/metabolismo , Síndrome de Job/genética , Síndrome de Job/imunologia , Mutação , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Receptor de Interferon alfa e beta/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia
19.
Eur Ann Allergy Clin Immunol ; 49(5): 231-234, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28884991

RESUMO

Summary: We describe the case of a 24-year-old male with hyper-IgE syndrome (HIES) which was diagnosed at 4 years of age and died from a very rare cardiac complication. He had typical clinical and laboratory manifestations of HIES, including total serum IgE as high as > 100,000 IU/mL. Stem cell transplantation was not available. During the 20-year follow-up, he suffered numerous various infections of the skin and deep organs, partial lung resection, as well as multiple bone fractures. At age 24, he developed acute decompensated heart failure associated with elevated serum troponin I and brain natriuretic protein. Two-dimensional echocardiogram revealed global hypokinesis of the left ventricle with estimated ejection fraction 20-25%, and catheterization revealed ectasia of multiple coronary arteries. Endomyocardial biopsy showed lymphocytic myocarditis, focal necrosis, mild fibrosis, and myxoid degeneration, but cultures were negative. The patient improved on corticosteroid therapy and was discharged on heart failure therapy and external defibrillator. Six weeks later, he developed supraventricular tachycardia and persistent global hypokinesis and was treated with amiodarone. A trial of intravenous immunoglobulin was initiated and was repeated as outpatient every four weeks for four times. However, his cardiac function did not improve and he developed severe hypotension and pulseless electrical activity arrest. Resuscitation was unsuccessful. To the best of our knowledge, this is the first reported case of HIES complicated with lymphocytic myocarditis. Both immunologists and cardiologists need to be aware of such a complication and practice caution in using immunosuppressants when the patient's immune status is markedly compromised.


Assuntos
Hipergamaglobulinemia/imunologia , Imunoglobulina E/imunologia , Síndrome de Job/imunologia , Miocardite/imunologia , Biópsia , Evolução Fatal , Humanos , Hipergamaglobulinemia/complicações , Hipergamaglobulinemia/diagnóstico , Hospedeiro Imunocomprometido , Imunoglobulina E/sangue , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Síndrome de Job/complicações , Síndrome de Job/diagnóstico , Masculino , Miocardite/diagnóstico , Miocardite/fisiopatologia , Miocardite/terapia , Resultado do Tratamento , Adulto Jovem
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