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1.
Iran J Allergy Asthma Immunol ; 15(4): 264-274, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27921406

RESUMO

Atopic dermatitis (AD) is a heterogeneous disease with regard to clinical phenotype and natural history. We investigated T cell subtypes and cytokine responses in peripheral blood and skin lesions of AD patients with various sensitivities. Immunological studies were performed in 27 subjects: 9 house dust mite (HDM)-sensitized; 6 subjects with sensitizations other than HDM; 7 non-allergic AD patients and 5 healthy controls. Among those, skin biopsy samples of 13 subjects were evaluated for immunohistochemical analyses, as well. The mean age was 8.93±5.17 years. HDM-allergic AD emerged as a distinct immunologic phenotype, with higher production of interleukin (IL)-4, -5, -2 both at rest and when stimulated by Der p1 or SEB along with higher Th17. As for TH17 cell percentage, it was increased in all AD groups compared to healthy controls, while HDM-allergic group was distinguished with a significantly lower production of IL-17. Patients with sensitizations other than HDM were mostly similar to non-allergic AD, with increased Th17 and CD4+CD69+interferon-gamma (IFN-γ)+ T cells percentage. The biopsy of lesional skin showed that HDM-allergic AD had lower IFN-γ and IFN-γ co-expressing CD8+ T cells compared to patients with other sensitizations (p=0.03 and p=0.04, respectively). Among the HDM allergic patients, pairwise comparison of lesional versus non-lesional skin revealed higher CD4+ T cells numbers, expression of forkhead box P3 (Foxp3) and T-cell-specific transcription factor (T-bet) (p=0.018, p=0.018, p=0.018, respectively). HDM-allergic AD is a distinct subtype with a predominant skewing in Th2 and higher Th17 cell percentage along with a blunted Th1 response in the skin, all of which may have therapeutic implications.


Assuntos
Antígenos de Dermatophagoides/administração & dosagem , Proteínas de Artrópodes/administração & dosagem , Cisteína Endopeptidases/administração & dosagem , Dermatite Atópica/imunologia , Pyroglyphidae/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adolescente , Animais , Criança , Pré-Escolar , Citocinas/imunologia , Dermatite Atópica/diagnóstico , Dermatite Atópica/patologia , Feminino , Humanos , Lactente , Masculino , Testes Cutâneos , Células Th17/patologia , Células Th2/patologia
2.
J Clin Immunol ; 36(7): 641-8, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27379765

RESUMO

PURPOSE: Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID). METHODS: Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer. RESULTS: Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4(+) T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-ß and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib. CONCLUSION: STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.


Assuntos
Mutação com Ganho de Função , Heterozigoto , Fator de Transcrição STAT1/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Idade de Início , Autoimunidade/genética , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Análise Mutacional de DNA , Feminino , Expressão Gênica , Genes Dominantes , Humanos , Isotipos de Imunoglobulinas/sangue , Isotipos de Imunoglobulinas/imunologia , Imunofenotipagem , Lactente , Infecção/diagnóstico , Infecção/etiologia , Interferon beta/metabolismo , Interferon beta/farmacologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Linhagem , Fosforilação , Pirazóis/farmacologia , Fator de Transcrição STAT1/metabolismo , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X , Turquia
3.
J Pediatr Hematol Oncol ; 37(8): 616-22, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26479985

RESUMO

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency was recently defined as a new severe congenital neutropenia subgroup remarkable with congenital heart defects, urogenital malformations, endocrine abnormalities, and prominent superficial veins. Here, we report 3 patients with G6PC3 deficiency presenting with recurrent diarrhea, failure to thrive, and sinopulmonary infections leading to bronchiectasis. In patient I and II, a combined immune deficiency was suspected due to early-onset disease with lymphopenia, neutropenia, and thrombocytopenia, along with variable reductions in lymphocyte subpopulations and favorable response to intravenous γ-globulin therapy. Apart from neutropenia, all 3 patients had intermittent thrombocytopenia, anemia, and lymphopenia. All patients had failure to thrive and some of the classic syndromic features of G6PC3 deficiency, including cardiac abnormalities and visibility of superficial veins in all, endocrinologic problems in PI and PIII, and urogenital abnormalities in PII. Our experience suggests that a diagnosis of congenital neutropenia due to G6PC3 may not be as straightforward in such patients with combined lymphopenia and thrombocytopenia. A high index of suspicion and the other syndromic features of G6PC3 were clues to diagnosis. Screening of all combined immune deficiencies with neutropenia may help to uncover the whole spectra of G6PC3 deficiency.


Assuntos
Anormalidades Múltiplas/genética , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo I/genética , Síndromes de Imunodeficiência/genética , Subpopulações de Linfócitos/patologia , Neutropenia/genética , Anormalidades Múltiplas/enzimologia , Adolescente , Bronquiectasia/etiologia , Domínio Catalítico , Linhagem da Célula , Criança , Códon sem Sentido , Colite/enzimologia , Colite/genética , Consanguinidade , Diarreia/enzimologia , Diarreia/genética , Éxons/genética , Insuficiência de Crescimento/enzimologia , Insuficiência de Crescimento/genética , Feminino , Mutação da Fase de Leitura , Doença de Depósito de Glicogênio Tipo I/imunologia , Humanos , Síndromes de Imunodeficiência/enzimologia , Linfopenia/congênito , Linfopenia/enzimologia , Linfopenia/genética , Masculino , Mutagênese Insercional , Neutropenia/enzimologia , Linhagem , Fenótipo , Sítios de Splice de RNA/genética , Infecções Respiratórias/complicações , Trombocitopenia/congênito , Trombocitopenia/enzimologia , Trombocitopenia/genética , Turquia
4.
J Clin Immunol ; 35(6): 523-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26233237

RESUMO

Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.


Assuntos
Antirreumáticos/administração & dosagem , Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos B/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Hidroxicloroquina/administração & dosagem , Células Matadoras Naturais/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteína Quinase C-delta/genética , Síndrome Linfoproliferativa Autoimune/tratamento farmacológico , Síndrome Linfoproliferativa Autoimune/genética , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Humanos , Lactente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Masculino , Mutação/genética
5.
Front Immunol ; 5: 340, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25101082

RESUMO

The Wiskott-Aldrich syndrome (WAS) is due to mutations of the WAS gene encoding for the cytoskeletal WAS protein, leading to abnormal downstream signaling from the T cell and B cell antigen receptors (TCR and BCR). We hypothesized that the impaired signaling through the TCR and BCR in WAS would subsequently lead to aberrations in the immune repertoire of WAS patients. Using next generation sequencing (NGS), the T cell receptor ß and B cell immunoglobulin heavy chain (IGH) repertoires of eight patients with WAS and six controls were sequenced. Clonal expansions were identified within memory CD4(+) cells as well as in total, naïve and memory CD8(+) cells from WAS patients. In the B cell compartment, WAS patient IGH repertoires were also clonally expanded and showed skewed usage of IGHV and IGHJ genes, and increased usage of IGHG constant genes, compared with controls. To our knowledge, this is the first study that demonstrates significant abnormalities of the immune repertoire in WAS patients using NGS.

6.
J Clin Immunol ; 34(6): 601-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24916357

RESUMO

PURPOSE: IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) is a rare X-linked recessive life-threatening disorder characterized by autoimmunity and early death. Pulmonary complication related with IPEX has not been elucidated exactly. Here, we report 4 IPEX patients, 3 of which died from severe pulmonary disease. METHODS: Clinical data and laboratory findings including autoantibodies, immunoglobulin levels as well as number of T, B and NK cells were evaluated. FOXP3 expression and T reg activity were analyzed. The FOXP3 gene was sequenced and RNA analysis was performed. RESULTS: Patient I (PI) presented with nephrotic syndrome at 3 years of age and then developed autoimmune hepatitis without eczema, enteropathy or high IgE and died at 9 years of age due to acute respiratory distress syndrome (ARDS). Two cousins of PI had the same hypomorphic splice site mutation leading to a deletion of 27 amino acids, but normal FOXP3 protein expression and normal suppressive capacity of T reg in a proliferation inhibition assay. However, they exhibited typical symptoms such as eczema, diabetes and enteropathy with eosinophilia at early age (PII, PIII) and were transplanted in infancy. One of them had severe respiratory distress right after birth (PIII). Patient IV from another family presented with chronic diarrhea without autoimmune manifestations and died due to ARDS. CONCLUSION: Lung disease related to IPEX syndrome has not been reported before and this entity could be a critical factor in disease outcome.


Assuntos
Fatores de Transcrição Forkhead/genética , Subpopulações de Linfócitos/imunologia , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Linfócitos T Reguladores/imunologia , Idade de Início , Autoanticorpos/sangue , Criança , Pré-Escolar , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/congênito , Diarreia , Evolução Fatal , Fatores de Transcrição Forkhead/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/congênito , Tolerância Imunológica/genética , Lactente , Masculino , Mutação/genética , Linhagem , Síndrome do Desconforto Respiratório do Adulto/epidemiologia , Síndrome do Desconforto Respiratório do Adulto/genética , Turquia
7.
Respir Med ; 107(9): 1322-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23886432

RESUMO

BACKGROUND: Although sublingual immunotherapy (SLIT) has been demonstrated to be a safe and efficient treatment in children with seasonal allergic rhinitis (AR), there is little evidence on the efficacy of SLIT with house-dust-mite (HDM) extract in children with isolated perennial AR. OBJECTIVES: We sought to assess the clinical efficacy and safety of HDM-SLIT in children with isolated allergic rhinitis-conjunctivitis mono-sensitized to HDM without asthma symptoms. METHODS: Twenty-two children (aged 5-10 years) with perennial AR and conjunctivitis symptoms mono-sensitized to Dermatophagoides pteronyssinus and Dermatophagoides farinae were enrolled. During a 2 months run-in period, symptom and medication scores, lung functions, bronchial hyperreactivity, nasal provocation and skin prick tests were evaluated. Subjects were randomized to active or placebo using a double-blind method. A total of eighteen subjects were randomised to receive either active SLIT or placebo for 12 months. Daily symptom and medication scores, baseline lung functions, bronchial hyperreactivity, nasal provocation and skin prick tests were recorded and re-evaluated at the end of treatment. RESULTS: After one year of treatment, no significant differences were detected in the between groups and within group comparisons based on total rhinitis symptom/medication scores (p > 0.05). Skin reactivity to Dermatophagoides pteronyssinus was significantly reduced in HDM-SLIT compared to placebo group (p = 0.018). A significant reduction in nasal sensitivity was observed in SLIT group after one year treatment when compared to baseline (p = 0.04). Total conjunctivitis symptoms were reduced significantly in both active and lacebo group at the end of treatment compared to baseline. The proportion of patients with non-specific bronchial hyperreactivity increased to almost 3-fold in placebo group compared to baseline. CONCLUSION: HDM-SLIT was not superior to placebo in reducing isolated rhinoconjunctivitis symptoms within 12 months of treatment. However, HDM-SLIT has a modulating effect on allergen-specific nasal and skin reactivity in isolated perennial AR children. CLINICAL TRIAL REGISTRATION: The trial was registered at Anzctr.org.au number, ACTRN12613000315718.


Assuntos
Alérgenos/administração & dosagem , Conjuntivite Alérgica/terapia , Pyroglyphidae/imunologia , Rinite Alérgica Perene/terapia , Imunoterapia Sublingual/métodos , Animais , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes de Provocação Nasal , Estudos Prospectivos , Testes de Função Respiratória , Testes Cutâneos , Resultado do Tratamento
8.
Gene ; 512(2): 189-93, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23124046

RESUMO

Protein tyrosine kinases (PTKs) play an important role in T cell development and activation. In vitro and in vivo defects, resulting in variable deficiencies in thymic development and in T cell antigen receptor (TCR) signal transduction, in PTKs have been shown. ZAP70, one of those PTKs, is a 70-kDa tyrosine phosphoprotein and associates with the ζ chain and undergoes tyrosine phosphorylation following TCR stimulation. It is expressed in T and natural killer (NK) cells. Several mutations were shown to lead to an autosomal recessive form of severe combined immunodeficiency disease (SCID). Here, we present a family with a novel mutation in ZAP70. The proband, the second child of the first cousin parents of Turkish origin, was diagnosed with SCID having R514C mutation on homozygous state. She had decreased CD8(+) T and natural killer cells, normal CD4(+) T cells, high serum Ig E level, perivascular dermatitis and ichthyosis. This article presents clinical features of a novel mutation on ZAP70 and the first prenatal molecular diagnosis of ZAP70 deficiency. Different mutations in ZAP70 and related phenotypes reported in the literature are also discussed.


Assuntos
Mutação de Sentido Incorreto , Diagnóstico Pré-Natal , Imunodeficiência Combinada Severa , Proteína-Tirosina Quinase ZAP-70/genética , Adulto , Substituição de Aminoácidos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Pré-Escolar , Dermatite/sangue , Dermatite/diagnóstico , Dermatite/genética , Dermatite/patologia , Família , Feminino , Humanos , Ictiose/sangue , Ictiose/diagnóstico , Ictiose/genética , Ictiose/patologia , Imunoglobulina E/sangue , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Masculino , Linhagem , Gravidez , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Turquia , Proteína-Tirosina Quinase ZAP-70/sangue , Proteína-Tirosina Quinase ZAP-70/deficiência
9.
Pediatr Allergy Immunol ; 22(7): 676-83, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21645119

RESUMO

BACKGROUND: Multiple factors in common variable immunodeficiency (CVID) might interfere with optimal growth and maturation and potentially compromise bone health. METHODS: We aimed to evaluate bone mineral density (BMD) of patients with CVID using dual energy X-ray absorptiometry (DEXA) and investigate risk factors associated with decreased bone density. RESULTS: Twenty-two patients were included (M: 16, F: 6) with a mean age of 15.6 ± 9.0 yr. DEXA revealed osteopenia in 6/22 (27.3%) and osteoporosis in 9/22 (40.9%) at lumbar spine and osteopenia in 7/19 (37%) and osteoporosis in 3/19 (16%) at femoral neck sites. The age of subjects with osteoporosis was significantly higher than those without (21.6 ± 8.0 vs. 9.0 ± 5.7 yr; p < 0.0001). BMD z-scores were significantly lower in patients with bronchiectasis compared with those without (p = 0.03). Patients with osteoporosis at femoral neck site had lower forced expiratory volume in 1 s (FEV(1) ) (p = 0.024), FEV(1) /forced vital capacity (FVC) (p < 0.0001), PEF (p = 0.008), and FEF 25-75 (p = 0.013) values compared with the patients with normal BMD z-scores. Low serum 25(OH) vitamin D levels were detected in 13/22 patients and low dietary calcium intake in 17/22 patients. BMD z-scores at femoral neck were lower in patients with low B-cell percentage (p = 0.03). BMD z-score at lumbar spine was correlated with folate (r = +0.63, p = 0.004) and serum immunoglobulin G levels (r = +0.430, p = 0.04). CONCLUSION: Osteoporosis appeared as an emerging health problem of patients with CVID, the risk increasing with older age and poorer lung function. Nutritional, biochemical, and immunologic factors appeared to take part in decreased BMD. Insight into the mechanisms of osteoporosis in CVID is crucial to develop preventive strategies.


Assuntos
Imunodeficiência de Variável Comum/complicações , Osteoporose/diagnóstico por imagem , Absorciometria de Fóton , Adolescente , Adulto , Densidade Óssea , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/epidemiologia , Bronquiectasia/complicações , Bronquiectasia/imunologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/imunologia , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Masculino , Osteoporose/complicações , Osteoporose/epidemiologia , Testes de Função Respiratória , Fatores de Risco , Adulto Jovem
10.
Pediatr Allergy Immunol ; 22(3): 298-304, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20961339

RESUMO

Childhood asthma is a heterogeneous condition with different phenotypes. Hereby, we aimed to study impact of serum immunoglobulin levels on clinical phenotypes and outcome of asthma. Seventy-eight children (M: 26, F: 52) aged less than 10 yrs (mean = 8.56 ± 3.23 yrs) and diagnosed as mild-moderate persistent asthma, followed up for at least 1 yr were included into the study. Asthmatic children were divided into two groups based on serum immunoglobulin levels at admission and were evaluated with respect to demographic data, allergic sensitization, symptom scores, medication usage, pulmonary functions, and non-specific bronchial hyper-reactivity. The age at onset of symptoms (40.88 ± 32.02 vs. 23.04 ± 26.97 months) was significantly younger in children with hypogammaglobulinemia (n = 28) compared to normogammaglobulinemia group (n = 50) (p = 0.016). Mean follow-up duration was 3.8 ± 2.1 yrs. Atopic sensitization rate was higher in those with normal immunoglobulin levels (81.2% vs. 17.9%), (p < 0.0001). Normal serum immunoglobulin levels were associated with atopic asthma (OR, 4.5; 95% confidence interval (CI): 2.0-10.1). For the prediction of atopic asthma, having normal immunoglobulin levels yielded predictive values of: sensitivity = 88.6%, specificity = 71.8%, positive predictive value = 81.1%, negative predictive value = 82.1%. Furthermore, percentages of atopic dermatitis and allergic conjunctivitis, elevated serum total IgE levels, eosinophilia, and bronchial hyper-reactivity were more common in normogammaglobulinemia with asthma group (p = 0.040, p = 0.003, p = 0.024, p = 0.030, p = 0.040, respectively). Although marked reductions in asthma scores and inhaled corticosteroid usage were observed in both groups over time, the rate of decline was significantly higher and earlier in hypogammaglobulinemia group (p = 0.0001, p = 0.004, respectively). In conclusion, asthmatic children with hypogammaglobulinemia presented at an earlier age, with lower rates of atopy, and earlier clinical improvement accompanied with earlier discontinuation of inhaled corticosteroids than children with normal immunoglobulin levels. Our data demonstrated that in children currently named as early-onset non-atopic asthma, hypogammaglobulinemia might be accompanying, providing evidence for a different phenotype of childhood asthma.


Assuntos
Agamaglobulinemia/complicações , Asma/complicações , Asma/fisiopatologia , Imunoglobulinas/sangue , Agamaglobulinemia/imunologia , Asma/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade Imediata/complicações , Hipersensibilidade Imediata/imunologia , Masculino , Valor Preditivo dos Testes , Prognóstico , Testes Cutâneos
11.
Pediatr Allergy Immunol ; 21(7): 1059-63, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20977501

RESUMO

To determine the optimal time of Bacillus Calmette-Guerin (BCG) vaccination for induction of Th1 immunity, we measured the interferon (IFN)-γ and interleukin (IL)-10 secretion in purified protein derivative (PPD)-stimulated peripheral blood mononuclear cell (PBMC) cultures in newborns vaccinated at birth or 2nd month of life. Moreover, role of CD4(+) CD25(+) T cells was studied by depletion assay at 8th month. Nineteen term and healthy newborns were randomized into two groups: Group I composed of 10 newborns vaccinated with BCG at birth and the remaining 9 (group II) at 2nd month of life. PBMCs were isolated at birth, 2nd and 8th months of age, and PPD-stimulated IL-10, 5 and IFN-γ secretion were assessed. The same measurements were repeated for IL-10 and IFN-γ after the depletion of CD4(+) CD25(+) T cells at the 8th month. Children vaccinated at birth demonstrated higher PPD-stimulated IFN-γ and IL-10 levels at 2 months of age when compared to non-vaccinated ones (p = 0.038 and p = 0.022, respectively), whereas at 8 months, no significant differences were detected between the two groups. Moreover, CD4(+) CD25(+)-depleted T-cell cultures resulted in lower PPD-stimulated IL-10 levels in those vaccinated at birth when compared to non-depleted condition at the 8th month (p < 0.001). BCG at birth upregulated PPD-stimulated IFN-γ secretion at the 2nd month and remained still detectable at 8 month after the vaccination, whereas those vaccinated at the 2nd month of life lacked that increase in IFN-γ response at the same time-point. Furthermore, depletion assays suggest that CD4(+) CD25(+) T cells are involved in PPD-stimulated IL-10 secretion in response to BCG vaccination.


Assuntos
Vacina BCG , Interleucina-10/biossíntese , Linfócitos T Reguladores/metabolismo , Antígenos CD4/biossíntese , Células Cultivadas , Feminino , Humanos , Lactente , Recém-Nascido , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Depleção Linfocítica , Masculino , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Tuberculina/imunologia , Tuberculina/metabolismo , Vacinação
12.
J Allergy Clin Immunol ; 124(2): 342-8, 348.e1-5, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19577286

RESUMO

BACKGROUND: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. OBJECTIVE: To elucidate mechanisms underlying different forms of HIES. METHODS: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. RESULTS: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. CONCLUSION: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.


Assuntos
Diferenciação Celular/imunologia , Interleucina-17/imunologia , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Imunoglobulina E/sangue , Lactente , Interferon-alfa/farmacologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-1/farmacologia , Interleucina-12/farmacologia , Interleucina-23/farmacologia , Interleucina-6/farmacologia , Interleucinas/farmacologia , Síndrome de Job/imunologia , Masculino , Mutação/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Receptores do Ácido Retinoico/imunologia , Receptores do Ácido Retinoico/metabolismo , Receptores dos Hormônios Tireóideos/imunologia , Receptores dos Hormônios Tireóideos/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos
13.
Pediatr Allergy Immunol ; 20(6): 545-50, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19140904

RESUMO

Previously, an inverse association was suggested between mycobacterial infection and atopy. We aimed to determine the association between tuberculin skin test (TST) and allergic manifestations in a birth cohort where all infants were vaccinated with bacillus Calmette-Guérin (BCG) at birth. Newborns were enrolled randomly and prospectively followed up for a period of 5 yr. Information on family history and environmental factors was obtained at birth, International Study of Asthma and Allergies in Childhood asthma questionnaire, physical examination, skin prick test to common inhalant and food allergens and TST were performed at 2 and 5 yr of age. Positive TST reactivity was defined as an induration of > or = 10 mm. A total of 399 newborns were enrolled, 293 and 125 were available for a followup visit at 2 and 5 yr of age respectively. The prevalence of ever asthma, rhinitis and allergen sensitization tended to increase while eczema decreased with time. No significant association was found between TST reactivity and ever and current wheeze, doctor diagnosed asthma or atopic sensitization both at 2 and 5 yr of age. This prospectively designed birth cohort study did not confirm the previously suggested inverse correlation between TST reactivity and atopic sensitization or any allergic manifestations in Turkish children vaccinated with BCG at birth.


Assuntos
Vacina BCG/administração & dosagem , Hipersensibilidade Imediata/imunologia , Teste Tuberculínico , Asma/diagnóstico , Asma/epidemiologia , Asma/imunologia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/epidemiologia , Lactente , Recém-Nascido , Masculino , Sons Respiratórios/diagnóstico , Rinite/diagnóstico , Rinite/epidemiologia , Rinite/imunologia , Testes Cutâneos , Tuberculose/prevenção & controle
14.
Pediatr Allergy Immunol ; 19(3): 248-54, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18397409

RESUMO

Data on the pathogenic mechanisms underlying the development of non-atopic asthma in children are scarce. Our aim was to evaluate the association and compare the atopic status, pulmonary functions, bronchial hyperresponsiveness and serum total immunoglobulin E (IgE) levels of parents of atopic and non-atopic asthmatic children by using objective methods. Fifty-one asthmatic children aged 4-16 yr and their parents were included into the study. Initially the American Thoracic Society's Respiratory Disease questionnaire inquiring data on symptoms of asthma, rhinitis and past medical history was filled in. Afterwards, skin prick test with aeroallergens, pulmonary function and methacholine bronchial provocation tests and serum sampling for total IgE level determinations were carried out. Bronchial hyperresponsiveness to methacholine was significantly more common in the mothers of non-atopic children compared to those of atopic ones, although no significant difference was observed in the skin prick test reactivity, pulmonary function test parameters and serum IgE levels. Questionnaire data revealed that the presence of asthmatic symptoms such as wheezing and phlegm and doctor-diagnosed asthma were more common in the mothers of non-atopic children. Meanwhile, asthmatic symptoms were also found to be significantly more common in fathers of non-atopic children. Logistic regression analyses revealed that maternal PC(20) was the only predictive factor for the risk of displaying non-allergic asthma in children. The results demonstrate that among the risk factors studied, maternal bronchial hyperreactivity was associated with the development of asthma in non-atopic children.


Assuntos
Asma/genética , Hiper-Reatividade Brônquica/genética , Imunoglobulina E/sangue , Rinite/genética , Adolescente , Adulto , Asma/epidemiologia , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Criança , Pré-Escolar , Saúde da Família , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Rinite/epidemiologia , Rinite/imunologia , Fatores de Risco
15.
Allergy Asthma Proc ; 29(4): 411-6, 2008 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18341761

RESUMO

Mucosal immunotherapy is suggested as a treatment strategy for tolerance induction in allergic diseases. The purpose of this study was to determine the effect of transferred splenic T cells from intranasal ovalbumin (OVA)-immunized mice to naive mice before sensitization on its impact of cytokine production and airway histopathology. BALB/c mice in group I received intranasal immunotherapy (days1-6), carboxylfluorescein succinyl ester (CFSE)-labeled splenocytes or splenic T cells were i.v. transferred to naive recipients (group II) before OVA sensitization. Acute murine asthma model was established by two i.p. OVA injections (days 21 and 28) and seven OVA nebulizations (days 42-48) in groups I, II and III. Groups III and IV served as asthma model and control, respectively. CFSE-labeled cells in splenocytes and lymph node lymphocytes, lung histopathology, IL-4, IL-10, and interferon (IFN) gamma cytokines of recipients were analyzed 24 hours after OVA nebulization challenge. CFSE-labeled T cells from group I were detected in spleen and regional lymph nodes of the OVA-sensitized recipients (group II). Smooth muscle and thickness of airways were less in intranasal OVA immunotherapy and OVA-sensitized recipients when compared with the asthma model (p < 0.05). Area of inflammation was significantly suppressed in OVA-sensitized recipients compared with the asthma model (p < 0.01). IL-10 and IFN-gamma levels in splenocyte supernatants were significantly increased in intranasal immunotherapy and OVA-sensitized recipients compared with asthma model and controls (p < 0.01). IL-4 levels were significantly less in intranasal immunotherapy group and the OVA-sensitized recipient group when compared with asthma the model group (p < 0.05). This study suggests that intranasal immunotherapy with allergens regulates T-cell responses and ameliorates airway histopathology in sensitized mice, hence, encouraging mucosal tolerance induction as a suitable treatment of allergic diseases.


Assuntos
Transferência Adotiva , Asma/prevenção & controle , Dessensibilização Imunológica , Tolerância Imunológica , Imunidade nas Mucosas , Pulmão/imunologia , Ovalbumina/imunologia , Linfócitos T/transplante , Administração Intranasal , Animais , Asma/imunologia , Asma/patologia , Células Cultivadas , Modelos Animais de Doenças , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Pulmão/patologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Baço/imunologia , Linfócitos T/imunologia
16.
Allergy Asthma Proc ; 29(1): 67-73, 2008 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18302841

RESUMO

The objective of this study was to evaluate the effect of intratracheal (i.t.) or subcutaneous (s.c.) Mycobacterium vaccae treatment on lung histopathology and cytokine responses in a murine model of asthma. BALB/c mice were divided into four groups. To establish an asthma model, Groups I, II and III received intraperitoneal (i.p.) ovalbumin (OVA) and were challenged with i.t. OVA three times (days 41-47). On the same days, mice in Groups I and II were treated with i.t. and s.c. Mycobacterium vaccae, respectively. Mice in Group IV served as controls. On day 49, lungs were taken out for histopathological evaluation. Cytokine levels were determined in splenocyte culture supernatants by ELISA. The thickness of basement membrane and hyperplasic goblet cells in small airways were found to be significantly more in Group III than Group I. Furthermore, smooth muscle and epithelial thickness in small and large airways and hyperplasic goblet cell numbers in all sized airways of this treatment group were not significantly different from controls. Epithelial thickness in medium and large airways, hyperplasic goblet cells in all sized airways, and basement membrane in small and large airways were not significantly different in Group II when compared to controls. OVA-stimulated IL-5 levels was significantly higher in Group I when compared to Group III. OVA-stimulated IL-5 and spontaneous IL-5 levels were significantly higher in Group II than Group III. We demonstrate that subcutaneous and intratracheal Mycobacterium vaccae administered along with allergen has an ameliorating effect in the modulation of airway histopathological changes in OVA sensitized mice.


Assuntos
Asma/terapia , Imunoterapia Ativa , Pulmão/patologia , Mycobacterium/imunologia , Animais , Asma/imunologia , Asma/patologia , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/uso terapêutico , Células Cultivadas , Feminino , Injeções Subcutâneas , Interferon gama/análise , Interleucina-10/análise , Interleucina-5/análise , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Baço/citologia , Baço/imunologia , Traqueia
17.
Immunopharmacol Immunotoxicol ; 30(1): 1-11, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18306100

RESUMO

Although the development of atopy in the newborn is determined by a multitude of factors, an intense Th1 stimulus early in life could be protective by facilitating a switch away from Th2. Aimed to determine the effect of single Mycobacterium vaccae (M. vaccae) immunization to OVA-sensitized pregnant mice on IL-5 and IFN-gamma secretion from placental lymphocytes and splenocytes of offspring. Pregnant BALB/c mice were divided into 4 groups, OVA-sensitized + M. vaccae immunized, OVA-sensitized, M. vaccae immunized and controls. Sensitization with OVA was initiated before mating, and aerosol OVA challenge were performed during pregnancy. M. vaccae immunization was performed on the 12(th) day of pregnancy. IL-5 and IFN-gamma levels of placental lymphocytes were analyzed on the 18(th) day of pregnancy and splenocytes of offspring on the 2(nd) and 28(th) days during postnatal period. A single administration of M. vaccae to OVA-sensitized pregnant mice downregulated IL-5 secretion and induced IFN-gamma secretion from placental lymphocytes. On the other hand, after M. vaccae immunization downregulation of IL-5 levels and upregulation of IFN-gamma secretion persisted in offspring when determined on 2(nd) and 28(th) days of life. Vaccination with M. Vaccae to OVA-sensitized pregnant BALB/c mice prevented Th2 immune responses by enhancing secretion of IFN-gamma and lowering IL-5 levels during pregnancy and the effect persisted during the postnatal period in offspring.


Assuntos
Asma/prevenção & controle , Interferon gama/metabolismo , Interleucina-5/metabolismo , Mycobacterium/imunologia , Hipersensibilidade Respiratória/prevenção & controle , Animais , Animais Recém-Nascidos , Asma/imunologia , Feminino , Imunização , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Placenta/imunologia , Gravidez , Hipersensibilidade Respiratória/imunologia , Células Th2/imunologia
18.
Pediatr Allergy Immunol ; 18(6): 508-15, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17680909

RESUMO

Although sublingual immunotherapy (SLIT) is accepted to be a viable alternative of specific-allergen immunotherapy, the efficacy of long-term SLIT in asthmatic children is not well established. The efficacy of 3 yr of SLIT in addition to pharmacotherapy was compared with pharmacotherapy alone in a prospective, open, parallel-group, controlled study. Children with asthma aged 4-16 yr, sensitive to house dust mite (HDM) were followed up for a run-in period of 1 yr and then grouped as those who would receive SLIT + pharmacotherapy (n = 62) or pharmacotherapy alone (n = 28). All patients were evaluated based on symptom-medication scores and lung function tests every 3 months, as well as skin-prick test and serum total immunoglobulin E (IgE) levels annually for 3 yr. Children in the SLIT + pharmacotherapy group demonstrated significantly lower mean daily dose and annual duration of inhaled corticosteroid (ICS) usage when compared with controls. At the end of the 3 yr, within-group comparisons revealed statistically significant decreases in the dose and duration of ICS only in the SLIT group. Furthermore, 52.4% of subjects in the SLIT + pharmacotherapy group were able to discontinue ICS treatment for at least 6 months, which was only 9.1% for the pharmacotherapy group. Three years of SLIT as an adjunct to pharmacotherapy resulted in reduction of both the duration and dose of ICSs and successful discontinuation of ICSs along with improvement in lung functions in HDM-allergic children with asthma.


Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Antígenos de Dermatophagoides/administração & dosagem , Asma/terapia , Dessensibilização Imunológica/métodos , Hipersensibilidade/terapia , Pyroglyphidae/imunologia , Administração por Inalação , Administração Sublingual , Adolescente , Corticosteroides/administração & dosagem , Animais , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Asma/imunologia , Budesonida/administração & dosagem , Budesonida/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Lactente , Masculino , Estudos Prospectivos , Testes de Função Respiratória , Testes Cutâneos , Fatores de Tempo , Resultado do Tratamento
19.
Ann Allergy Asthma Immunol ; 98(6): 573-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17601272

RESUMO

BACKGROUND: Mycobacteria are being investigated for modulation of inflammation in asthma and atopic disorders by eliciting particularly strong protective TH1 immune responses. OBJECTIVE: To investigate the long-term effects of intratracheally administered Mycobacterium vaccae on an experimental murine model of asthma. METHODS: BALB/c mice were placed in 4 groups: long-term M. vaccae, M. vaccae, asthma, and control groups. All groups but controls were sensitized intraperitoneally and challenged intratracheally with ovalbumin. The long-term M. vaccae and M. vaccae groups were treated with M. vaccae intratracheally simultaneously during challenges. Finally, mice in the long-term M. vaccae group were rechallenged with ovalbumin nebulization 24 days later. Evaluations of lung histopathologic findings and serum cytokine levels were performed. RESULTS: Comparison of the long-term M. vaccae group with the asthma model group revealed that the number of hyperplasic goblet cells in small and large airways (small airway: P < .05; large airways: P < .01) and thickness of basement membrane in large airways were significantly less in the long-term M. vaccae group. Furthermore, numbers of hyperplasic goblet cells in small airways (P < .05) and basement membrane in the large airway (P < .05), as well as inflammation in small airways (P < .01), were significantly less in the M. vaccae group when compared with the asthma model group. Interferon-gamma secretion from splenocytes of the M. vaccae group was significantly higher than the asthma model and long-term M. vaccae groups. CONCLUSION: Intratracheal administration of M. vaccae exerted a long-lasting ameliorating effect on airway histopathologic features of a murine asthma model.


Assuntos
Asma/imunologia , Asma/patologia , Mycobacterium/imunologia , Animais , Asma/prevenção & controle , Membrana Basal/patologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Células Caliciformes/patologia , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso/patologia , Ovalbumina/imunologia , Fatores de Tempo
20.
Allergy Asthma Proc ; 28(2): 174-82, 2007 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17479601

RESUMO

The aim of this study was to investigate the association between parasitosis and allergy. We surveyed all children aged 4-12 years living in poor hygienic conditions in a shantytown of Istanbul. After obtaining data from the International Study of Asthma and Allergies in Childhood (ISAAC) and an additional questionnaire, performing a skin-prick test (SPT), and determining total IgE, stool and perianal tape specimens were obtained from 1018 participating children. The prevalence of past episodes of wheezing, current wheezing, asthma, and rhinitis was 31, 14.6, 10.7, and 26.2%, respectively. Parasitosis was present in 49.1%, Enterobius vermicularis (23.3%), being the most common. A history of treatment for enterobiasis was present in 37%. Comparison of children with and without current enterobiasis revealed no significant difference in allergic manifestations and SPT results, except for serum total IgE level (p = 0.018), whereas children with previous enterobiasis were more likely to have current wheezing (p = 0.012). Current wheezers were more likely to have previous enterobiasis (p = 0.01) and a higher maternal employment level (p = 0.036) when compared with those without. According to logistic regression analysis, covariables significantly positively related with current wheezing were previous enterobiasis (p = 0.003) and being < or =5 years of age (p = 0.043), whereas being the first child of the family (p = 0.043) was negatively related. A previous infection with E. vermicularis was found to potentiate current wheezing in a population living in a shantytown in Istanbul.


Assuntos
Enterobíase/complicações , Hipersensibilidade/complicações , Hipersensibilidade/parasitologia , Sons Respiratórios/etiologia , População Urbana , Asma/complicações , Asma/parasitologia , Criança , Pré-Escolar , Estudos Transversais , Enterobíase/diagnóstico , Enterobíase/epidemiologia , Fezes/parasitologia , Feminino , Habitação , Humanos , Higiene , Hipersensibilidade/diagnóstico , Hipersensibilidade/epidemiologia , Imunoglobulina E/sangue , Modelos Logísticos , Masculino , Razão de Chances , Prevalência , Rinite Alérgica Perene/complicações , Rinite Alérgica Perene/parasitologia , Rinite Alérgica Sazonal/complicações , Rinite Alérgica Sazonal/parasitologia , Medição de Risco , Fatores de Risco , Testes Cutâneos , Inquéritos e Questionários , Turquia/epidemiologia , População Urbana/estatística & dados numéricos
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