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1.
Minerva Pediatr ; 69(4): 274-280, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26365745

RESUMO

BACKGROUND: There is limited data for predicting the risk of exacerbations following the cessation of inhaled corticosteroids (ICS) in well controlled childhood asthma. In current study, clinical, functional and inflammatory parameters at the time of ICS withdrawal were investigated in that respect. METHODS: Forty children asymptomatic for at least 3 months on low dose ICS's were enrolled and ICS were discontinued in summer. At enrolment symptom/medication diary, pulmonary function parameters, methacholine provocation testing, peripheral blood eosinophilia, serum total and allergen-specific IgE levels and skin prick testing were performed. In a subgroup of patients, phytohemaglutinin induced secretion of IL-5, IL-13, IFN-γ and IL-10 from blood mononuclear cells were measured. Patients were assessed with symptom/medication diary and pulmonary function test every 2 months for 6 months. RESULTS: Eighteen of 37 patients experienced recurrence of acute asthma symptoms. In patients with acute attack (group I), changes in rhinitis symptom scores at 2nd month vs. baseline were statistically higher. In addition, group I had significantly higher rhinitis symptom scores compared to group II at fourth-month visit. Patients with acute exacerbation revealed a significant decrease in FEV1% at 2nd month compared to baseline. Moreover, group I showed significantly lower FEF 25-75% compared to group II at 2nd month. Baseline bronchial hyper-responsiveness with methacholine was found to be an independent risk factor for asthma exacerbation. CONCLUSIONS: The findings of this study identified baseline bronchial hyperreactivity, higher rhinitis symptom scores and gradual decrease in pulmonary function parameters during follow-up as risk factors for subsequent exacerbation of asthma.


Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Hiper-Reatividade Brônquica/epidemiologia , Glucocorticoides/administração & dosagem , Administração por Inalação , Asma/fisiopatologia , Criança , Pré-Escolar , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Masculino , Fluxo Máximo Médio Expiratório , Recidiva , Testes de Função Respiratória , Rinite/epidemiologia , Fatores de Risco
2.
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
3.
Balkan Med J ; 33(5): 539-542, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27761282

RESUMO

BACKGROUND: Allergic diseases with a potential for anaphylaxis pose a critical public health issue in schools. AIMS: This study was carried out to identify the current status of prevention and management of anaphylaxis in school children with the main goal of establishing such an action plan. STUDY DESIGN: Cross-sectional study. METHODS: Schools were randomly selected from 11 different regions of Istanbul. A questionnaire was filled out by 2596 teachers/school principals from 232 public schools. RESULTS: A school safety committee was absent in 80% of elementary schools (ES) and 60.8% of preschools (PS). Although some form of health recording system was available in many schools, no such system was available in 24.5% of ESs and 10% of PSs. A specific inquiry for detecting children with food allergies was a routine practice in only 4% of ES and 10% of PS. Approximately 27% of teachers stated that monitoring children in school places was not possible at all times. Eighty four percent stated that no written anaphylaxis treatment protocol was available in their school and only around 2.3% in ES and 3.1% in PS stated that they would perform an epinephrine injection in the event of anaphylaxis. CONCLUSION: Our survey demonstrated critical gaps in the organization of schools for the management of children at risk of anaphylaxis. Data derived from this study would provide the initiative for legislators to review the current situation of school health policies along with the relevant authorities to establish school anaphylaxis guidelines.

4.
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
5.
Turk Pediatri Ars ; 51(1): 8-14, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27103859

RESUMO

AIM: Immunoglobulin replacement therapy is required to reduce the frequency and severity of infections in patients with primary antibody deficiencies. Immunoglobulin G (IgG) can be administered intramuscularly, intravenously or subcutaneously. We aimed to evaluate the efficacy, dose adjustment and adverse events in subcutaneous immunoglobulin therapy by retrospectively presenting the records of 16 patients who received subcutaneous immunoglobulin therapy. MATERIAL AND METHODS: The demographic findings, clinical and laboratory findings, subcutaneous immunoglobulin dosage and dose frequency, infusion time, area and methods, adverse events and frequency of infections were obtained from patient files and recorded. RESULTS: Sixteen patients (seven female, nine male) aged between 0-33 years who were diagnosed with primary immune deficiency and treated with subcutaneous immunoglobulin were enrolled. All patients had been receiving intravenous imunoglobulin (5-10%) at a dose of 0.33-1.25 gr/kg/dose with two-four week intervals before subcutaneous immunoglobulin. Subcutaneous immunoglobulin (10%) was administered at a dose of 0.03-0.43 gr/kg/dose with one-two week intervals. No significant difference was found between serum through IgG levels before administration of intravenous imunoglobulin and steady state IgG levels during subcutaneous immunoglobulin therapy. When five patients whose serum through IgG levels were below 600 mg/dL were evaluated, however, a significant increase was found in steady state IgG levels with subcutaneous immunoglobulin therapy (p=0.043). In a ten-month follow-up period, seven infections were observed in four patients (three upper respiratory infectons, two lower respiratory tract infections and three acute gastroenteritis). No acute severe bacterial infection was observed. Local advers reaction was reported in only 10 of 180 infusions (6%). No serious adverse events were reported. All 16 patients were willing to continue IgG replacement therapy by subcutaneous administration. CONCLUSIONS: Ig replacement therapy by subcutaneous route is an efficient, safe and easy option which is eligible for individual administration. Home therapy is feasible for patients with primary immune deficiency, if informed consent is obtained and sufficient education is ensured.

6.
J Allergy Clin Immunol ; 138(1): 241-248.e3, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26936803

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.


Assuntos
Doença Granulomatosa Crônica/complicações , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Vacina BCG/administração & dosagem , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/mortalidade , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/mortalidade , Micoses/diagnóstico , Micoses/epidemiologia , Micoses/etiologia , Micoses/mortalidade , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Tuberculose/diagnóstico , Tuberculose/etiologia
7.
Eur J Pediatr ; 175(5): 685-93, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26833050

RESUMO

UNLABELLED: The severity and duration of immunosuppression caused by corticosteroids (CSs) usage have not been extensively studied. We aimed to investigate the effects of CSs on the various compartments of immune system in relation to timing of initiation and persistence of therapy. Pediatric patients with idiopathic nephrotic syndrome (NS) treated with 2 mg/kg/day prednisolone and healthy control (HC) were enrolled. Blood samples were drawn for immunologic analyses at baseline and at the first and second weeks and first, second, and third months of CS therapy in addition to first and second weeks and first, second, and third months of discontinuation. Fourteen patients (M/F, 7/7) between 1 and 8 years old were evaluated. Untreated NS exhibited high absolute lymphocyte count (ALC)(p = 0.010), absolute CD3(+) T cells (p = 0.020) and absolute CD8(+) T cells (p = 0.006) compared to HC. Suppression in ALC was observed and nadir value was noted at first month of therapy compared to baseline (p = 0.002). The CD4(+) (p = 0.036) and CD8(+) T cell (p = 0.013) counts decreased significantly at the first week of treatment compared to baseline. While baseline B cell counts was indifferent from HC, gradually increased in 2 weeks of CS initiation and decreased during the treatment with a statistical significance compared to HC (p = 0.010). However, after cessation of CS, B cell counts continued to decline and found to be significantly different than baseline at first week (p = 0.008) and at third month (p = 0.040). CONCLUSION: Apart from baseline lymphocyte subset changing observed in untreated NS patients, our data implies that T cells were suppressed very early in the CS treatment. Interestingly, depressed B cell counts were detected later but persisted even after CS cessation. Due to early decrease in T cells, it would be beneficial to assume the patients as immunosuppressed at the very beginning of CS treatment to avoid infections. WHAT IS KNOWN: • Corticosteroids (CSs) are widely used for a variety of diseases including nephrotic syndrome, which is related with complex immune disturbance including T and B cells dysfunctions. • CSs induce neutrophilic leukocytosis concomitant with lymphopenia and eosinopenia leading to immunosupression. What is New: • T cell subsets and proliferation are susceptible to CSs more than B cells; however, the reversibility is faster with dose reduction in CS. • The change of B cells and B cell subtypes (CD27 (+) memory) shows prolonged effect of CSs on B cells which may alter antibody production even after 3 months of CSs cessation.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Imunossupressão/métodos , Síndrome Nefrótica/imunologia , Prednisolona/administração & dosagem , Biópsia , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/administração & dosagem , Humanos , Lactente , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
8.
Minerva Pediatr ; 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26763692

RESUMO

AIM: The immunomodulatory effects of vitamin B12 deficiency in children have not yet been established in the literature. In the current study, the effects of vitamin B12 on the immune system in asymptomatic and otherwise healthy infants have been studied. METHODS: The study was conducted at Marmara University, "well-child" outpatient clinic. Vitamin B12 level was measured in a cohort of 611 healthy term infants, followed regularly for at least 6 months. Immunoglobulin measurements, lymphocyte subset analysis, cytokine production analysis, lymphocyte proliferation assays and evaluation of lymphocyte apoptosis were performed in a subset of 60 infants. RESULTS: In this cohort, one out of three babies displayed vitamin B12 deficiency. The percentage of CD4+CD25+ regulatory T cells (Tregs) was lower in vitamin B12 deficient babies than in controls. Although the percentage of Tregs increased after treatment, the change was not significant. There was no difference of cytokine levels between vitamin B12 deficient and control groups. However, proinflammatory cytokines were reduced after treatment. No significant difference was observed for immunoglobulins, early apoptosis and lymphocyte proliferation. CONCLUSION: Vitamin B12 deficiency is an underestimated health problem among the developing countries. The clinical consequences of the decreased percentage of Tregs associated with vitamin B12 deficiency, and reduction of proinflammatory cytokines after vitamin supplementation needs to be further studied, especially in terms of emerging allergies, autoimmune disorders and anti-inflammatory effects.

10.
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
11.
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
12.
J Exp Med ; 211(13): 2537-47, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25488983

RESUMO

Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8(+) T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434-475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α-p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.


Assuntos
Processamento Alternativo/genética , Genes Dominantes , Síndromes de Imunodeficiência/enzimologia , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Formação de Anticorpos , Sequência de Bases , Linfócitos T CD8-Positivos/imunologia , Domínio Catalítico , Diferenciação Celular , Pré-Escolar , Ativação Enzimática , Éxons/genética , Feminino , Heterozigoto , Humanos , Síndromes de Imunodeficiência/imunologia , Transtornos Linfoproliferativos/enzimologia , Transtornos Linfoproliferativos/imunologia , Masculino , Dados de Sequência Molecular , Linhagem , Fosfatidilinositol 3-Quinases/química , Estrutura Terciária de Proteína , Deleção de Sequência , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Telômero/metabolismo
13.
J Allergy Clin Immunol ; 134(6): 1365-1374, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25218284

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is typified by recurrent infections, increased serum IgE levels, eosinophilia, and a high incidence of allergic and autoimmune manifestations. OBJECTIVE: We sought to determine the role of DOCK8 in the establishment and maintenance of human B-cell tolerance. METHODS: Autoantibodies were measured in the plasma of DOCK8-deficient patients. The antibody-coding genes from new emigrant/transitional and mature naive B cells were cloned and assessed for their ability to bind self-antigens. Regulatory T (Treg) cells in the blood were analyzed by means of flow cytometry, and their function was tested by examining their capacity to inhibit the proliferation of CD4(+)CD25(-) effector T cells. RESULTS: DOCK8-deficient patients had increased levels of autoantibodies in their plasma. We determined that central B-cell tolerance did not require DOCK8, as evidenced by the normally low frequency of polyreactive new emigrant/transitional B cells in DOCK8-deficient patients. In contrast, autoreactive B cells were enriched in the mature naive B-cell compartment, revealing a defective peripheral B-cell tolerance checkpoint. In addition, we found that Treg cells were decreased and exhibited impaired suppressive activity in DOCK8-deficient patients. CONCLUSIONS: Our data support a critical role for DOCK8 in Treg cell homeostasis and function and the enforcement of peripheral B-cell tolerance.


Assuntos
Linfócitos B/imunologia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/imunologia , Síndromes de Imunodeficiência/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Autoanticorpos/sangue , Criança , Pré-Escolar , Feminino , Humanos , Tolerância Imunológica/imunologia , Lactente , Contagem de Linfócitos , Masculino
14.
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.

15.
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
16.
Int Immunopharmacol ; 22(1): 31-40, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24957687

RESUMO

New strategies are needed to suppress airway inflammation and prevent or reverse airway remodeling in asthma. Reprogramming induced pluripotent stem cells (iPSCs) have the potential of embryonic stem cells (ESCs) and provide a resource for stem cell-based utility. The aim of this study was to evaluate the histopathological and immunomodulatory effects of ESCs and iPSCs for potential allogenic application in a murine model of acute asthma. BALB/c mice were sensitized with alum-absorbed ovalbumin (OVA) and then challenged with 1% aerosolized OVA. 5×10(5) ESCs and iPSCs were administrated intranasally on the last day of nebulization. Mice were sacrificed after 24 h, and serum allergen specific antibody level, airway remodeling, cytokine levels in lung supernatants, and eosinophilic infiltration in BAL fluid were examined. As a result, more ESCs and iPSCs integrated into the lungs of mice in OVA groups than those of the controls. Epithelial, smooth muscle and basal membrane thicknesses as well as goblet cell hyperplasia occurring in airway remodeling were significantly suppressed by pluripotent stem cells in both distal and proximal airways. Percentage of eosinophils decreased significantly in BAL fluid as well as serum allergen-specific IgE and IL-4 levels in lung supernatants. On the contrary, regulatory cytokine - IL-10 level - was enhanced. Application of especially ESCs significantly increased the percentage of Treg subsets. Our comparative results showed that i.n. delivery of miRNA-based reprogrammed iPSCs is beneficial in attenuating airway inflammation in a murine model of acute asthma, and that cells also have similar immunomodulatory effects in mice.


Assuntos
Asma/terapia , Células-Tronco Embrionárias/fisiologia , Células Caliciformes/patologia , Pulmão/imunologia , Células-Tronco Pluripotentes/fisiologia , Transplante de Células-Tronco , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Doença Aguda , Remodelação das Vias Aéreas , Animais , Asma/imunologia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Células-Tronco Embrionárias/transplante , Eosinófilos/imunologia , Humanos , Hiperplasia , Imunoglobulina E/sangue , Imunossupressão , Pulmão/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Células-Tronco Pluripotentes/transplante , Pneumonia , Transplante Homólogo
18.
J Allergy Clin Immunol ; 132(5): 1156-1163.e5, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23910690

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22(phox), p47(phox), p67(phox), and p40(phox) of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91(phox) leads to X-linked recessive CGD. OBJECTIVE: The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. METHODS: We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. RESULTS: Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A22(0), A67(0) or X91(0) phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47(phox)-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index ≥ 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. CONCLUSION: Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A22(0) and A67(0) subtypes manifests as severe as the X91(0) subtype.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Causas de Morte , Pré-Escolar , Ativação Enzimática , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/mortalidade , Humanos , Incidência , Infecção/etiologia , Masculino , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/metabolismo , Análise de Sequência de DNA
19.
J Asthma ; 50(9): 938-44, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23919566

RESUMO

OBJECTIVE: Risk factors related to the outcome of childhood asthma are not yet well established. We aimed to investigate the long-term outcome for children with asthma to determine the risk factors in predicting persistence of disease. METHODS: Sixty-two children with asthma were evaluated retrospectively at the end of a 10-year follow-up. Patients were asked to complete a questionnaire requesting clinical information, and underwent physical examination, skin prick testing, a pulmonary function test and bronchial provocation testing. Immunologic parameters evaluated were allergen-specific IgE and IgG4 levels, and allergen-induced generation of CD4(+)CD25(+) cells. RESULTS: Mean age at final assessment was 15.9 ± 3.6 years, and duration of follow-up was 10.30 ± 1.27 years. Fifty percent of patients outgrew their asthma during the 10-year follow-up period. All the non-atopic patients outgrew their disease during the study period, whereas 67% of atopic patients did not. We identified two risk factors independently related to the persistence of symptoms: presence of bronchial hyper-responsiveness and presence of rhinitis. Atopic children who were in remission demonstrated significantly higher allergen-induced CD4(+)CD25(+) T cells compared to healthy controls. CONCLUSIONS: Atopy, presence of rhinitis, positive and presence of bronchial hyper-reactivity are important risk factors for the persistence of asthma in children. Allergen-induced CD4(+)CD25(+) T cells were higher in the atopic children who outgrew their disease, implicating an immunological mechanism of asthma remission in children.


Assuntos
Asma/imunologia , Hipersensibilidade Imediata/imunologia , Hipersensibilidade/imunologia , Adolescente , Asma/fisiopatologia , Testes de Provocação Brônquica , Feminino , Seguimentos , Humanos , Hipersensibilidade/fisiopatologia , Hipersensibilidade Imediata/fisiopatologia , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Leucócitos Mononucleares/imunologia , Modelos Logísticos , Masculino , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de Risco , Testes Cutâneos , Inquéritos e Questionários
20.
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
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