RESUMO
BACKGROUND: Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. METHODS: We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. RESULTS: The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47-54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6-5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06-10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10-0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30-0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24-1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. CONCLUSION: Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Asma/diagnóstico , Asma/epidemiologia , Citocinas/sangue , Feminino , Humanos , Hipersensibilidade Imediata/epidemiologia , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/metabolismo , Imunização , Estudos Longitudinais , Masculino , Razão de Chances , Prevalência , Fatores de RiscoRESUMO
BACKGROUND: Cytokines play a pivotal role in regulating the development and persistence of the inflammatory process in asthma. Our aim was to investigate whether asthma persistence or remission is associated with a specific cytokine profile. METHODS: The Tasmanian Longitudinal Health Study followed participants from 7 to 44 years of age. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10 and tumor necrosis factor-alpha (TNF-α) were measured at age 44 years. Participants were categorized into five phenotypes (early-onset noncurrent asthma, early-onset current asthma, late-onset noncurrent asthma and late-onset current asthma). Those who had never had asthma formed the reference group. Multivariable linear regression was used to compare serum cytokine concentrations between each phenotype and the reference group. RESULTS: IL-10 concentrations were significantly lower in serum from the early-onset current asthma group than in the reference group (ratio of geometric means 0.58; 95% confidence interval 0.33-0.99; p = 0.048). IL-6 concentrations for the late-onset remitted group were also significantly lower than in the reference group (p = 0.009). The TNF-α concentrations were significantly lower for both early-and late-onset remitted asthma phenotypes when compared with the reference group. No associations were detected between serum concentrations of IL-4, IL-5 or IL-8 and these specific longitudinal asthma phenotypes. CONCLUSION: Our findings suggest a possible role for deficient IL-10 responses in the persistence of early-onset asthma. Lower IL-6 and TNF-α concentrations in serum from those with remitted asthma suggest that these proinflammatory cytokines may be actively suppressed during asthma remission.
Assuntos
Asma/epidemiologia , Asma/imunologia , Citocinas/sangue , Mediadores da Inflamação/sangue , Adolescente , Adulto , Idade de Início , Criança , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Remissão Espontânea , Tasmânia/epidemiologia , Adulto JovemRESUMO
BACKGROUND: With the increasing burden of asthma worldwide, much effort has been given to developing and updating management guidelines. Using data from the Tasmanian Longitudinal Health Study (TAHS), the adequacy of asthma management for middle-aged adults with asthma was investigated. METHODS: Information about spirometry, medication history and current asthma status was collected by the most recent TAHS when participants were in their mid 40s. Only those who reported ever having asthma were eligible for analysis. RESULTS: Of the 702 participants who reported ever having asthma, 50% had current asthma (n = 351) of whom 71% were categorised as having persistent asthma (n = 98 mild, n = 92 moderate, n = 58 severe). The majority (85.2%) of participants with current asthma had used some form of asthma medication in the past 12 months, but the proportion of the use of minimally adequate preventer medication was low (26%). Post-bronchodilator airflow obstruction increased progressively from mild to severe persistent asthma for those inadequately managed, but not for those on adequate therapy. CONCLUSION: Appropriate use of asthma medication by this middle-aged group of adults with current asthma was inadequate, especially for those with adult-onset moderate or severe persistent disease and without a family history of asthma. These results suggest that proper use of preventer medication could protect against the progressive decline in lung function associated with increasing severity. This has implications not just for poor quality of life, but also for the development of fixed airflow obstruction.
Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Cooperação do Paciente , Guias de Prática Clínica como Assunto , Adulto , Asma/fisiopatologia , Asma/prevenção & controle , Uso de Medicamentos/estatística & dados numéricos , Métodos Epidemiológicos , Feminino , Volume Expiratório Forçado , Glucocorticoides/administração & dosagem , Fidelidade a Diretrizes/estatística & dados numéricos , Humanos , Masculino , Autoadministração/normas , Tasmânia , Capacidade VitalRESUMO
We have investigated the expression of cell surface markers and leucocyte cell adhesion molecules by immunohistochemistry in bronchial biopsies from 10 mild atopic asthmatics and 8 normal, nonatopic subjects. Significantly increased numbers of eosinophils (p<0.01) were evident in the bronchial submucosa of asthmatic subjects. In epithelium there were more CD44+ (p<0.02) and lymphocyte function-associated antigen-1 (LFA-1)+ (p<0.06) leucocytes in asthmatics than in normal subjects. Bronchial epithelial cells stained positively with anti-CD44 monoclonal antibodies (moAb) in both groups; however, when the staining was expressed as percentage of the total basement membrane, a considerable and highly significant increase was observed in the asthmatics (median 80 vs 22%, p=0.003). Few leucocytes were positive for very late activation antigen (VLA)-1, VLA-2 and VLA-4. The moAb for VLA-6 stained the basement membrane of the bronchial epithelium; while intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were constitutively expressed in endothelium. A positive correlation was found between LFA-1+ cells and activated eosinophils (EG2+) in the submucosa (p<0.005; r(s)=0.80). We conclude that even in mild asthma there is evidence of increased expression of cell surface ligands, and suggest that adhesive mechanisms play a role both in cell recruitment and disease activity.
Assuntos
Asma/metabolismo , Brônquios/metabolismo , Receptores de Hialuronatos/análise , Integrinas/análise , Adulto , Asma/patologia , Eosinófilos , Epitélio/química , Feminino , Humanos , Imuno-Histoquímica , Integrina alfa1beta1 , Integrina alfa4beta1 , Integrina alfa6beta1 , Integrina beta1/análise , Molécula 1 de Adesão Intercelular/análise , Contagem de Leucócitos , Antígeno-1 Associado à Função Linfocitária/análise , Masculino , Pessoa de Meia-Idade , Mucosa/metabolismo , Fenótipo , Receptores de Colágeno , Receptores de Retorno de Linfócitos/análiseRESUMO
BACKGROUND: Bronchial challenge with allergen causes a specific form of airways inflammation consisting of an influx of neutrophils, eosinophils, and T cells. Because the relevance of the challenge model to clinical asthma is uncertain, the cellular changes that occur in the lungs of asthmatic subjects during natural seasonal allergen exposure were investigated. METHODS: Seventeen grass pollen sensitive asthmatic subjects with previously reported seasonal exacerbations of asthma kept records of symptoms and underwent fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy before and during the peak of the grass pollen season. The BAL cells were analysed for differential cell counts and by flow cytometry for T cell subsets and surface activation markers. The biopsy samples were processed into glycol methacrylate resin and immunohistochemical analysis was performed for mast cells, activated eosinophils, T cells and interleukin 4 (IL-4), a cytokine with a pivotal role in allergen-induced inflammation. RESULTS: In the pollen season there was an increase in T lymphocyte activation in the BAL fluid as identified by increased expression of interleukin 2 receptor (IL-2R). In the submucosa these changes were paralleled by an increase in CD4+ T cells. By contrast, the numbers of metachromatic cells in BAL fluid staining with toluidine blue were reduced, possibly because of degranulation following allergen stimulation. In keeping with mast cell activation, the number of mucosal mast cells staining for secreted IL-4 increased during the season. In comparison with the period shortly before the onset of the season, all but two subjects experienced an asthma exacerbation which followed the rise in pollen counts but, compared with the period preceding the first bronchoscopic examination, asthma symptoms were not increased during the pollen season. CONCLUSIONS: The data suggest that natural allergen exposure, leading to a clinical exacerbation of asthma, may induce an inflammatory response involving T cells, mast cells and eosinophils. The relationship between allergen exposure, cellular infiltration and activation, and clinical symptoms appears to be complex, with factors other than allergen also contributing to asthmatic activity.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Pulmão/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Adulto , Brônquios/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Eosinófilos/imunologia , Feminino , Humanos , Ativação Linfocitária , Masculino , Mastócitos/imunologia , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologiaRESUMO
Seasonal allergic rhinitis is characterized by the development of nasal mucosal inflammation in response to natural allergen exposure, and is prevented by the administration of topical corticosteroids. Interleukin-4 (IL-4), IL-5, and IL-6 may have important roles in this process, and in vitro the gene transcription for each of these cytokines is inhibited by corticosteroids. In this study we have therefore investigated the effect of seasonal allergen exposure on the expression of immunoreactivity for IL-4, IL-5, and IL-6 in nasal mucosal biopsies, and the effect of regular prophylactic treatment with the topical corticosteroid, fluticasone propionate. Following a nasal mucosal biopsy out of season, patients were randomized double-blind to receive 6 wk of treatment during the pollen season with either topical fluticasone nasal spray (200 micrograms daily) or matching placebo. Each subject underwent a repeat nasal biopsy at the end of the 6-wk treatment period. Seasonal increases in epithelial eosinophils (p = 0.046), submucosal eosinophils (p = 0.001), and epithelial mast cells (p = 0.055) occurred in the placebo--but not the fluticasone-treated patients. Submucosal mast cell numbers did not change in either group. Immunoreactivity for IL-4 and IL-6 was localized predominantly to mast cells while IL-5 was found in both mast cells and eosinophils. Numbers of IL-4+ cells in the nasal submucosa were significantly suppressed by treatment with fluticasone (p = 0.0003 for monoclonal antibody [mAb] 3H4, p = 0.041 for mAb 4D9). In contrast, fluticasone treatment failed to influence the number of IL-5 and IL-6 immunoreactive cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Androstadienos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Interleucinas/análise , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Intranasal , Adulto , Método Duplo-Cego , Eosinófilos/patologia , Feminino , Fluticasona , Glucocorticoides , Humanos , Imuno-Histoquímica , Interleucina-4/análise , Interleucina-5/análise , Interleucina-6/análise , Masculino , Mastócitos/patologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Rinite Alérgica Sazonal/imunologiaRESUMO
Allergic mucosal inflammation is characterized by tissue infiltration with eosinophils, and associated activation of mast cells and T lymphocytes. Tumour necrosis factor (TNF) alpha/cachectin is a candidate cytokine relevant to the pathogenesis of these events through its capacity to upregulate the expression of endothelial cell adhesion molecules, mediate granulocyte chemoattraction, and activate eosinophils, mast cells and T cells. To investigate the presence and localization of TNF alpha in the nasal mucosa in allergic rhinitis, nasal biopsies from perennial rhinitic (n = 13) and non-rhinitic volunteers (n = 11) were embedded in glycol methacrylate and immunostained with a monoclonal antibody directed against TNF alpha, and adjacent 2 microns sections stained for tryptase, CD3 and eosinophil cationic protein. This identified positive immunostaining for TNF alpha in the submucosa of both the rhinitic and normal subjects (median cell counts 13 and 23 cells/mm2 respectively, P = 0.24) with cellular localization to mast cells but not to T-lymphocytes or eosinophils. In a subsequent study of seven atopic subjects, nasal allergen challenge produced increases in lavage levels of histamine and albumin, which was associated with significant release of TNF alpha as early as 2 min post-allergen when compared with the saline control day (P = 0.05). This difference was also apparent when studying the area under the curve both at 30 and 60 min post-challenge t-test (P = 0.015 and 0.02 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Mastócitos/metabolismo , Mucosa Nasal/metabolismo , Rinite Alérgica Perene/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Albuminas/metabolismo , Biópsia , Quimases , Eosinófilos/imunologia , Feminino , Histamina/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/farmacologia , Masculino , Mastócitos/imunologia , Líquido da Lavagem Nasal/química , Mucosa Nasal/imunologia , Rinite Alérgica Perene/imunologia , Rinite Alérgica Perene/fisiopatologia , Serina Endopeptidases/metabolismo , Triptases , Fator de Necrose Tumoral alfa/imunologiaAssuntos
Citocinas/biossíntese , Mastócitos/patologia , Mucosa Nasal/metabolismo , Rinite Alérgica Perene/metabolismo , Adulto , Biópsia , Feminino , Humanos , Hipersensibilidade Imediata/metabolismo , Hipersensibilidade Imediata/patologia , Interleucina-4/metabolismo , Masculino , Mastócitos/metabolismo , Mucosa Nasal/patologia , Rinite Alérgica Perene/patologiaRESUMO
BACKGROUND: Local hyperthermia reduces mast cell degranulation, the severity of acute lung injury, and exercise-induced asthma and decreases symptoms of rhinitis. We have investigated the effect of local hyperthermia on mast cell degranulation and symptom generation in allergic rhinitis to assess its effect and mechanism of action within the nose. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 10 subjects with rhinitis were treated for 30 minutes with local hyperthermia or placebo, which was followed 30 minutes later by nasal allergen challenge. During the first two visits nasal lavages were performed to assess vascular leakage and mediator release. During the last two visits nasal airway resistance, the number of sneezes, and mucus secretion were monitored. RESULTS: Local hyperthermia significantly reduced both nasal airway resistance (p < 0.05) and vascular leakage (p < 0.02) but had no significant effect on the number of sneezes, on mucus secretion, or on tryptase release. CONCLUSION: Local hyperthermia reduces allergen-provoked nasal blockage and vascular leakage but has no effect on sneezing, rhinorrhea, or tryptase release. Nasal blockage occurs predominantly via newly formed lipid mediators and kinins, whereas sneezing and rhinorrhea occur predominantly via preformed mediators. We propose that local hyperthermia inhibits newly formed mediator production or release or reduces the sensitivity of the vasculature to inflammatory mediators in general. Further investigation into the mechanisms and potential uses of local hyperthermia is warranted.
Assuntos
Hipertermia Induzida , Mucosa Nasal/fisiopatologia , Rinite Alérgica Sazonal/terapia , Adulto , Resistência das Vias Respiratórias , Permeabilidade Capilar , Quimases , Método Duplo-Cego , Feminino , Humanos , Masculino , Mastócitos/enzimologia , Mucosa Nasal/irrigação sanguínea , Mucosa Nasal/imunologia , Testes de Provocação Nasal , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/fisiopatologia , Serina Endopeptidases/análise , TriptasesRESUMO
Allergic mucosal inflammation is characterized by the presence of cell infiltration, predominantly with IgE-sensitized mast cells and activated eosinophils, and appears to be regulated by the local production and release of several cytokines, particularly IL-4 and IL-5. Although attention has focused on the Th2 subpopulation of CD4+ T lymphocytes as an important source of these cytokines, human mast cells have been shown to both store and secrete IL-4 and TNF-alpha. To investigate the expression of cytokines relevant to allergic inflammation and to identify their cellular localization within the nasal mucosa, we have undertaken specific immunohistochemical staining of thin sections of inferior turbinate biopsies from patients with perennial allergic rhinitis and, for comparison, from nonatopic healthy volunteers. The cytokines investigated were IL-4, IL-5, IL-6, and IL-8. In both the normal and rhinitic biopsies numerous cells immunoreactive for IL-4, IL-5, and IL-6 were seen. Staining of adjacent 2-microns sections for CD3, mast cell tryptase, and eosinophil cationic protein revealed that 90% of the IL-4 immunoreactive cells were mast cells, with biopsies from rhinitic subjects containing significantly more IL-4+ cells than biopsies from normal controls (p = 0.02), especially when assessed with the anti-IL-4 mAb 3H4. Mast cells also accounted for > 90% of IL-6 and > 50% of IL-5 immunoreactive cells. IL-5 immunoreactivity was also localized to eosinophils, whereas IL-8 localized predominantly to the nasal epithelium in both groups. No cytokines were found in association with T lymphocytes. These findings indicate that the mast cell is an important source of preformed cytokines and as such may contribute to the chronicity of the mucosal inflammation that characterizes allergic rhinitis.
Assuntos
Interleucinas/análise , Mastócitos/imunologia , Mucosa Nasal/imunologia , Rinite Alérgica Perene/imunologia , Adulto , Feminino , Humanos , Imuno-Histoquímica , Interleucina-4/análise , Interleucina-4/imunologia , Interleucina-5/análise , Interleucina-5/imunologia , Interleucina-6/análise , Interleucina-6/imunologia , Interleucina-8/análise , Interleucina-8/imunologia , Interleucinas/biossíntese , Masculino , Linfócitos T/imunologiaRESUMO
Recent attention has focused on the T helper type 2 (Th2) lymphocyte as a source of interleukin 4 (IL-4) in allergic disease. However, Th2 cells themselves require a pulse of IL-4 to initiate this synthesis. Here we provide immunohistochemical evidence of IL-4 localization to human mast cells of the skin and respiratory tract, and demonstrate that immunoglobulin E-dependent stimulation of purified human lung mast cells leads to the rapid release of IL-4 into the extracellular environment. We propose that mast cell activation in an allergic response provides a rapid and local pulse of IL-4 into the local environment essential for the triggering of T lymphocytes into sustained IL-4 production and to initiate inflammatory cell accumulation and activation.
Assuntos
Interleucina-4/metabolismo , Mastócitos/metabolismo , Técnicas de Cultura , Humanos , Imuno-Histoquímica , Interleucina-4/análise , Interleucina-4/imunologiaRESUMO
Accumulating evidence supports the importance of leukocyte-endothelial cell adhesion molecule (CAM) expression as an initiating process in tissue inflammation. To investigate the relevance of CAM expression to allergic airways inflammation, nasal biopsies from patients with perennial allergic rhinitis (n = 8) and from nonatopic healthy volunteers (n = 8) were immunostained with monoclonal antibodies directed against the CAMs, intercellular adhesion molecule-1 (ICAM-1), endothelial cell adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1). The endothelial staining of these CAMs was related to the number of vessels within each biopsy, delineated by a monoclonal antibody against Ulex europaeus-1 lectin bound to endothelial cells, and to the number of tissue leukocytes staining for one of the ligands of ICAM-1, the beta 2 integrin, lymphocyte function-associated antigen (LFA-1). Expression of CAMs was related to the number of infiltrating neutrophils, eosinophils, and lymphocytes identified immunohistochemically within the biopsies. ICAM-1 was the most prominent CAM present on the endothelium of the normal nasal mucosa, with less expression of ELAM-1 and only minimal or absent expression of VCAM-1. In perennial rhinitis, both ICAM-1 (P less than 0.05) and VCAM-1 (P less than 0.01) expression on endothelial cells were increased and were positively correlated in their level of expression (P less than 0.002). The number of tissue LFA-1-positive cells was significantly greater (P less than 0.05) in the biopsies from the perennial rhinitics (median, 27.3/mm2) than from the healthy controls (median, 5.3 cells/mm2). LFA-1 expression significantly correlated with the number of ICAM-1-positive vessels (P less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Moléculas de Adesão Celular/biossíntese , Mucosa Nasal/fisiopatologia , Rinite Alérgica Perene/fisiopatologia , Adulto , Anticorpos Monoclonais , Biópsia , Moléculas de Adesão Celular/análise , Selectina E , Feminino , Humanos , Inflamação , Molécula 1 de Adesão Intercelular , Antígeno-1 Associado à Função Linfocitária/análise , Antígeno-1 Associado à Função Linfocitária/biossíntese , Masculino , Mucosa Nasal/patologia , Mucosa Nasal/fisiologia , Valores de Referência , Rinite Alérgica Perene/patologia , Molécula 1 de Adesão de Célula VascularRESUMO
Frusemide has recently been shown to antagonise exercise-induced bronchospasm, an action attributed to blockade of chloride channels in the bronchial epithelium. In order to test the hypothesis that frusemide non-specifically antagonises bronchospasm, we tested the bronchial reactivity to inhaled histamine in ten subjects aged 22 to 35 years, after nebulising 30 mg of frusemide, and after nebulising the frusemide vehicle (water at pH 9.1). The geometric mean (histamine PD20) after inhalation of the solution was 0.6 mumol and after frusemide was 0.45 mumol. The mean difference in PD20 between control and frusemide was -0.50 mumol (frusemide test more reactive) but this change was not statistically significant. We conclude that nebulised frusemide does not antagonise histamine-induced bronchospasm, and that the ability of frusemide to block exercise-induced bronchospasm may be specific to that stimulus.