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1.
Allergy ; 75(1): 84-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31267528

RESUMO

BACKGROUND: Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high-altitude treatment on the clinical and immunological response in asthma. METHODS: Twenty-six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood using flow cytometry. RESULTS: The number of eosinophils (both resting and activated) and chemoattractant receptor homolog expressed on Th2 cells (CRTH2)-expressing CD4+ and CD8+ T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2+ Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2-expressing ILC2, CD4+ and CD8+ T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2+ Tregs which partially normalized during high-altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2+ Treg cells in EA patients. Serum IL-5 and IL-13 decreased during climate treatment in asthma patients with high baseline levels. CONCLUSIONS: Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions.

2.
Allergy ; 74(12): 2394-2405, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31269238

RESUMO

BACKGROUND: Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent. METHODS: To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls. RESULTS: Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138+ plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE+ plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. Peripheral blood IgE+ memory B-cell frequencies were increased in STAT3-HIES, while other memory B-cell frequencies except for IgG4+ cells were decreased. CONCLUSIONS: Despite impaired STAT3 signaling, STAT3-HIES patients can mount in vivo T-cell-dependent B-cell responses, while circulating memory B cells, except for those expressing IgG4 and IgE, were reduced. Reduced molecular maturation demonstrated the critical need of STAT3 signaling for optimal affinity maturation and B-cell differentiation, supporting the need for immunoglobulin substitution therapy and explaining the high IgE serum level in the majority with absent allergic symptoms.

3.
Allergy ; 74(9): 1691-1702, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30793327

RESUMO

BACKGROUND: Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper-IgE syndrome (STAT3-HIES). The aim of this study was to expand knowledge about lung disease in STAT3-HIES. METHODS: The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3-HIES patients were assessed. RESULTS: The patients' quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive-restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ATP-binding cassette sub-family A member 3 (ABCA3) positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long-term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function. CONCLUSIONS: Due to its severity, pulmonary disease in STAT3-HIES patients requires strict monitoring and intensive therapy.

4.
J Allergy Clin Immunol Pract ; 7(3): 848-855, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.

5.
Sci Rep ; 8(1): 16719, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425284

RESUMO

In hyper-IgE syndromes (HIES), a group of primary immunodeficiencies clinically overlapping with atopic dermatitis, early diagnosis is crucial to initiate appropriate therapy and prevent irreversible complications. Identification of underlying gene defects such as in DOCK8 and STAT3 and corresponding molecular testing has improved diagnosis. Yet, in a child and her newborn sibling with HIES phenotype molecular diagnosis was misleading. Extensive analyses driven by the clinical phenotype identified an intronic homozygous DOCK8 variant c.4626 + 76 A > G creating a novel splice site as disease-causing. While the affected newborn carrying the homozygous variant had no expression of DOCK8 protein, in the index patient molecular diagnosis was compromised due to expression of altered and wildtype DOCK8 transcripts and DOCK8 protein as well as defective STAT3 signaling. Sanger sequencing of lymphocyte subsets revealed that somatic alterations and reversions revoked the predominance of the novel over the canonical splice site in the index patient explaining DOCK8 protein expression, whereas defective STAT3 responses in the index patient were explained by a T cell phenotype skewed towards central and effector memory T cells. Hence, somatic alterations and skewed immune cell phenotypes due to selective pressure may compromise molecular diagnosis and need to be considered with unexpected clinical and molecular findings.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Íntrons/genética , Síndrome de Job/genética , Mutação , Sítios de Splice de RNA/genética , Sequência de Bases , Pré-Escolar , Biologia Computacional , Feminino , Regulação da Expressão Gênica/genética , Humanos , Lactente , Síndrome de Job/patologia , Técnicas de Diagnóstico Molecular , Gravidez , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética
7.
PLoS One ; 12(10): e0186632, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29045479

RESUMO

BACKGROUND: Climate change affects human health. The respective consequences are predicted to increase in the future. Patients with chronic lung disease are particularly vulnerable to the involved environmental alterations. However, their subjective perception and reactions to these alterations remain unknown. METHODS: In this pilot study, we surveyed 172 adult patients who underwent pulmonary rehabilitation and 832 adult tourists without lung disease in the alpine region about their perception of being affected by climate change and their potential reaction to specific consequences. The patients' survey also contained the COPD Assessment Test (CAT) to rate the severity of symptoms. RESULTS: Most of the patients stated asthma (73.8%), COPD (9.3%) or both (11.0%) as underlying disease while 5.8% suffered from other chronic lung diseases. Patients and tourists feel equally affected by current climate change in general, while allergic subjects in both groups feel significantly more affected (p = 0.04). The severity of symptoms assessed by CAT correlates with the degree of feeling affected (p<0.01). The main disturbing consequences for patients are decreased air quality, increasing numbers of ticks and mosquitos and a rising risk for allergy and extreme weather events such as thunderstroms, while tourists are less disturbed by these factors. Increasing number of heat-days is of little concern to both groups. CONCLUSION: Overall patients are more sensitive to health-related consequences of climate change. Yet, the hazard of heat-days seems underestimated and awareness should be raised.


Assuntos
Mudança Climática , Percepção , Doença Pulmonar Obstrutiva Crônica/psicologia , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica/diagnóstico , Estatísticas não Paramétricas
8.
Pediatr Allergy Immunol ; 28(8): 768-775, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28981975

RESUMO

BACKGROUND: Rehabilitational programs at moderate altitude (1500-2500 m) showed improvement of lung function and reduction in airways inflammation in asthmatic adults. Allergen avoidance was postulated as the major cause of these improvements. METHODS: Spirometries of 344 and fractional exhaled nitric oxide measurements (FeNO) of 124 asthmatic children and adolescents, staying in a rehabilitation hospital in Davos (1590 m) with at least 14 days between admission and discharge, were analyzed in association with atopic sensitization (skin-prick testing and/or specific IgE), level of asthma control, and inhalative corticosteroid (ICS) dose. RESULTS: Pulmonary conditions improved significantly on average during the sojourn. Uncontrolled asthmatics benefited most with an absolute increase in predicted FEV1 , MEF25 , and MEF75 of 7.7%, 9.9%, and 12.7%, respectively (P < .001). FeNO decreased by 36.9 ppb for uncontrolled, by 26.9 ppb for partly controlled, and by 11.8 ppb for controlled asthmatics. In uncontrolled subjects, pulmonary improvement was comparable between patients with and without house dust mites (HDM) sensitization. Pulmonary improvements of pollen-sensitized patients were not dependent on the season of the sojourn. For the group with constant ICS level, the absolute increase in FEV1 was 4.9% (P < .001) with a FeNO decreased by 32.7 ppb (P < .001). When the ICS dose was elevated by one GINA level, the absolute increase in FEV1 was slightly higher (6.6%, P < .001), with a FeNO decrease of 31.4 ppb (P < .001). CONCLUSION: Inpatient rehabilitation at moderate altitude improved pulmonary conditions in asthmatic children and adolescents independent of sensitization status to HDM or pollen. A positive effect was also observed in patients without change in medication.


Assuntos
Altitude , Asma/fisiopatologia , Asma/reabilitação , Pulmão/fisiopatologia , Óxido Nítrico/metabolismo , Espirometria , Adolescente , Asma/diagnóstico , Asma/metabolismo , Biomarcadores/metabolismo , Testes Respiratórios , Criança , Pré-Escolar , Feminino , Seguimentos , Volume Expiratório Forçado , Hospitalização , Humanos , Pulmão/metabolismo , Masculino , Estudos Retrospectivos , Adulto Jovem
9.
Clin Infect Dis ; 64(9): 1279-1282, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28203787

RESUMO

STAT3 hyper-IgE syndrome (STAT3-HIES) patients presented with significantly lower Staphylococcus aureus-specific serum IgG compared to cystic fibrosis patients despite recurrent S. aureus infections. Immunoglobulin replacement therapy increased S. aureus-specific IgG in STAT3-HIES patients and attenuated the clinical course of disease suggesting a role of humoral immunity in S. aureus clearance.


Assuntos
Anticorpos Antibacterianos/sangue , Imunoglobulina G/sangue , Síndrome de Job/complicações , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Blood ; 127(25): 3154-64, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27114460

RESUMO

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.


Assuntos
Candidíase Mucocutânea Crônica/genética , Estudos de Associação Genética , Mutação , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
11.
Pediatr Allergy Immunol ; 27(2): 177-84, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26592211

RESUMO

BACKGROUND: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by elevated serum IgE, eczema, and recurrent infections. Despite the availability of confirmatory molecular diagnosis of several distinct HIES entities, the differentiation of HIES particularly from severe forms of atopic dermatitis remains a challenge. The two most common forms of HIES are caused by mutations in the genes STAT3 and DOCK8. METHODS: Here, we assess the clinical and immunologic phenotype of DOCK8- and STAT3-HIES patients including the cell activation, proliferation, and cytokine release after stimulation. RESULTS: Existing HIES scoring systems are helpful to identify HIES patients. However, those scores may fail in infants and young children due to the age-related lack of clinical symptoms. Furthermore, our long-term observations showed a striking variation of laboratory results over time in the individual patient. Reduced memory B-cell counts in concert with low specific antibody production are the most consistent findings likely contributing to the high susceptibility to bacterial and fungal infection. In DOCK8-HIES, T-cell lymphopenia and low IFN-gamma secretion after stimulation were common, likely promoting viral infections. In contrast to STAT3-HIES, DOCK8-HIES patients showed more severe inflammation with regard to allergic manifestations, elevated activation markers (HLA-DR, CD69, CD86, and CD154), and significantly increased inflammatory cytokines (IL1-beta, IL4, IL6, and IFN-gamma). CONCLUSION: Differentiating HIES from other diseases such as atopic dermatitis early in life is essential for patients because treatment modalities differ. To expedite the diagnosis process, we propose here a diagnostic workflow.


Assuntos
Dermatite Atópica/diagnóstico , Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/diagnóstico , Mutação/genética , Fator de Transcrição STAT3/genética , Linfócitos B/imunologia , Células Cultivadas , Pré-Escolar , Citocinas/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulina E/sangue , Memória Imunológica , Lactente , Síndrome de Job/genética , Ativação Linfocitária/genética , Masculino , Linfócitos T/imunologia
13.
J Am Soc Nephrol ; 25(6): 1291-302, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24511136

RESUMO

A pathogenic role for Th17 cells in inflammatory renal disease is well established. The mechanisms underlying their counter-regulation are, however, largely unknown. Recently, Th17 lineage-specific regulatory T cells (Treg17) that depend on activation of the transcription factor Stat3 were identified. We studied the function of Treg17 in the nephrotoxic nephritis (NTN) model of crescentic GN. The absence of Treg17 cells in Foxp3(Cre)×Stat3(fl/fl) mice resulted in the aggravation of NTN and skewing of renal and systemic immune responses toward Th17. Detailed analysis of Stat3-deficient Tregs revealed that the survival, activation, proliferation, and suppressive function of these cells remained intact. However, Tregs from Foxp3(Cre)×Stat3(fl/fl) mice lacked surface expression of the chemokine receptor CCR6, which resulted in impaired renal trafficking. Furthermore, aggravation of NTN was reversible in the absence of Th17 responses, as shown in CD4(Cre)×Stat3(fl/fl) mice lacking both Treg17 and Th17 cells, suggesting that Th17 cells are indeed the major target of Treg17 cells. Notably, immunohistochemistry revealed CCR6-bearing Treg17 cells in kidney biopsy specimens of patients with GN. CCR6 expression on human Treg17 cells also appears dependent on STAT3, as shown by analysis of Tregs from patients with dominant-negative STAT3 mutations. Our data indicate the presence and involvement of Stat3/STAT3-dependent Treg17 cells that specifically target Th17 cells in murine and human crescentic GN, and suggest the kidney-specific action of these Treg17 cells is regulated by CCR6-directed migration into areas of Th17 inflammation.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Glomerulonefrite/imunologia , Fator de Transcrição STAT3/imunologia , Células Th17/imunologia , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Movimento Celular/imunologia , Modelos Animais de Doenças , Glomerulonefrite/patologia , Humanos , Rim/imunologia , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR6/imunologia , Receptores CCR6/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Baço/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/patologia
14.
J Allergy Clin Immunol ; 133(2): 529-34, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24139496

RESUMO

BACKGROUND: Primary immunodeficiency (PID) disorders are a heterogeneous group of inherited disorders caused by a variety of monogenetic immune defects. Thus far, mutations in more than 170 different genes causing PIDs have been described. A clear genotype-phenotype correlation is often not available, which makes a genetic diagnosis in patients with PIDs complex and laborious. OBJECTIVE: We sought to develop a robust, time-effective, and cost-effective diagnostic method to facilitate a genetic diagnosis in any of 170 known PID-related genes by using next-generation sequencing (NGS). METHODS: We used both targeted array-based and in-solution enrichment combined with a SOLiD sequencing platform and a bioinformatic pipeline developed in house to analyze genetic changes in the DNA of 41 patients with PIDs with known mutations and 26 patients with undiagnosed PIDs. RESULTS: This novel NGS-based method accurately detected point mutations (sensitivity and specificity >99% in covered regions) and exonic deletions (100% sensitivity and specificity). For the 170 genes of interest, the DNA coverage was greater than 20× in 90% to 95%. Nine PID-related genes proved not eligible for evaluation by using this NGS-based method because of inadequate coverage. The NGS method allowed us to make a genetic diagnosis in 4 of 26 patients who lacked a genetic diagnosis despite routine functional and genetic testing. Three of these patients proved to have an atypical presentation of previously described PIDs. CONCLUSION: This novel NGS tool facilitates accurate simultaneous detection of mutations in 161 of 170 known PID-related genes. In addition, these analyses will generate more insight into genotype-phenotype correlations for the different PID disorders.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Síndromes de Imunodeficiência/genética , Análise de Sequência de DNA , Adolescente , Adulto , Criança , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/diagnóstico , Masculino , Mutação
15.
J Clin Immunol ; 33(6): 1088-99, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23708964

RESUMO

PURPOSE: This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. METHODS: NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. RESULTS: Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. CONCLUSION: The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.


Assuntos
Núcleo Celular/metabolismo , Displasia Ectodérmica/imunologia , Fibroblastos/imunologia , Quinase I-kappa B/metabolismo , Síndromes de Imunodeficiência/imunologia , Poliendocrinopatias Autoimunes/imunologia , Transporte Ativo do Núcleo Celular/genética , Pré-Escolar , Citocinas/imunologia , Células HeLa , Humanos , Quinase I-kappa B/genética , Lactente , Ativação Linfocitária/genética , Masculino , Mutação de Sentido Incorreto/genética , Proteólise , Células Th17/imunologia , Transgenes/genética
16.
J Clin Immunol ; 33(5): 896-902, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23584561

RESUMO

PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. Healing of pneumonias is often abnormal with formation of pneumatoceles and bronchiectasis. We aimed to explore whether healing after lung surgery is also aberrant. METHODS: We retrospectively analyzed the medical records of 32 patients with AD-HIES who received lung surgery for the management of pulmonary infections from 1960 to 2011. We collected information including patient demographics, STAT3 mutation status, clinical history, surgical and medical procedures performed, complications, related medical treatments, and outcomes. RESULTS: More than 50% of lung surgeries had associated complications, with the majority being prolonged bronchopleural fistulae. These fistulae often led to empyemas that necessitated additional interventions including prolonged antibiotics, prolonged thoracostomy tube drainage and re-operations. CONCLUSION: Lung surgery in AD-HIES patients is associated with high complication rates. STAT3 mutations likely lead to abnormalities in tissue remodelling that are further exacerbated by infection.


Assuntos
Síndrome de Job/imunologia , Síndrome de Job/fisiopatologia , Pneumopatias/fisiopatologia , Pneumopatias/cirurgia , Cicatrização/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Pulmão/imunologia , Pulmão/fisiopatologia , Pulmão/cirurgia , Pneumopatias/genética , Pneumopatias/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Fator de Transcrição STAT3/genética , Cicatrização/genética , Adulto Jovem
17.
J Allergy Clin Immunol ; 131(3): 840-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23380217

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. OBJECTIVES: We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. METHODS: A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. RESULTS: DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. CONCLUSIONS: DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy.


Assuntos
Actinas/imunologia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndromes de Imunodeficiência/imunologia , Células Matadoras Naturais/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Lactente , Células K562 , Masculino
19.
Pediatr Hematol Oncol ; 29(7): 585-94, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22897717

RESUMO

Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Condicionamento Pré-Transplante , Pré-Escolar , Análise Mutacional de DNA , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Síndromes de Imunodeficiência/imunologia , Mutação , Linhagem , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo
20.
Nat Med ; 18(4): 538-46, 2012 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-22447074

RESUMO

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell-intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow-resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T(H)2 cytokine-dependent inflammation and allergic disease.


Assuntos
Antibacterianos/uso terapêutico , Basófilos/citologia , Basófilos/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hipersensibilidade/imunologia , Inflamação/imunologia , Animais , Anticorpos/uso terapêutico , Antígenos CD/metabolismo , Basófilos/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/genética , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação/tratamento farmacológico , Linfonodos/citologia , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/imunologia , Células Th2/efeitos dos fármacos
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