RESUMO
In areas where Streptococcus pneumoniae is highly endemic, infants experience very early pneumococcal colonization of the upper respiratory tract, with carriage often persisting into adulthood. We aimed to explore whether newborns in high-risk areas have pre-existing pneumococcal-specific cellular immune responses that may affect early pneumococcal acquisition. Cord blood mononuclear cells (CBMC) of 84 Papua New Guinean (PNG; high endemic) and 33 Australian (AUS; low endemic) newborns were stimulated in vitro with detoxified pneumolysin (dPly) or pneumococcal surface protein A (PspA; families 1 and 2) and compared for cytokine responses. Within the PNG cohort, associations between CBMC dPly and PspA-induced responses and pneumococcal colonization within the first month of life were studied. Significantly higher PspA-specific interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-10 and IL-13 responses, and lower dPly-IL-6 responses were produced in CBMC cultures of PNG compared to AUS newborns. Higher CBMC PspA-IL-5 and PspA-IL-13 responses correlated with a higher proportion of cord CD4 T cells, and higher dPly-IL-6 responses with a higher frequency of cord antigen-presenting cells. In the PNG cohort, higher PspA-specific IL-5 and IL-6 CBMC responses were associated independently and significantly with increased risk of earlier pneumococcal colonization, while a significant protective effect was found for higher PspA-IL-10 CBMC responses. Pneumococcus-specific cellular immune responses differ between children born in pneumococcal high versus low endemic settings, which may contribute to the higher risk of infants in high endemic settings for early pneumococcal colonization, and hence disease.
Assuntos
Sangue Fetal/imunologia , Sangue Fetal/microbiologia , Imunidade Celular/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Anticorpos Antibacterianos/imunologia , Células Apresentadoras de Antígenos/imunologia , Antígenos de Bactérias/imunologia , Austrália , Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Células Cultivadas , Citocinas/imunologia , Feminino , Humanos , Recém-Nascido , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Papua Nova Guiné , Infecções Pneumocócicas/microbiologia , Gravidez , RiscoRESUMO
BACKGROUND: Prior studies have suggested a relationship between atopy and mental health, although methodological barriers have limited the generalizability of these findings. The objective of this study was to investigate the relationship between early-life atopy and vulnerability to mental health problems among youth in the community. METHOD: Data were drawn from the Raine Study (N = 2868), a population-based birth cohort study in Western Australia. Logistic regression and generalized estimating equations were used to examine the relationship between atopy at ages 1-5 years [using parent report and objective biological confirmation (sera IgE)], and the range of internalizing and externalizing mental health problems at ages 5-17 years. RESULTS: Atopy appears to be associated with increased vulnerability to affective and anxiety problems, compared to youth without atopy. These associations remained significant after adjusting for a range of potential confounders. No relationship was evident between atopy and attention deficit hyperactivity disorder or externalizing problems. CONCLUSIONS: Findings are the first linking atopy (measured by both parent report and objective verification) with increased vulnerability to affective and anxiety problems. Therefore, replication is required. If replicated, future research aimed at understanding the possible biological and/or social and environmental pathways underlying these links is needed. Such information could shed light on shared pathways that could lead to more effective treatments for both atopy and internalizing mental health problems.
Assuntos
Transtornos de Ansiedade/epidemiologia , Hipersensibilidade Imediata/epidemiologia , Transtornos do Humor/epidemiologia , Hipersensibilidade Respiratória/epidemiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Suscetibilidade a Doenças , Humanos , Lactente , Austrália Ocidental/epidemiologiaRESUMO
BACKGROUND: Epidemiological evidence suggests that routine vaccinations can have nontargeted effects on susceptibility to infections and allergic disease. Such effects may depend on age at vaccination, and a delay in pertussis vaccination has been linked to reduced risk of allergic disease. We aimed to test the hypothesis that delay in vaccines containing diphtheria-tetanus-acellular pertussis (DTaP) is associated with reduced risk of food allergy and other allergic diseases. METHODS: HealthNuts is a population-based cohort in Melbourne, Australia. Twelve-month-old infants were skin prick-tested to common food allergens, and sensitized infants were offered oral food challenges to determine food allergy status. In this data linkage study, vaccination data for children in the HealthNuts cohort were obtained from the Australian Childhood Immunisation Register. Associations were examined between age at the first dose of DTaP and allergic disease. RESULTS: Of 4433 children, 109 (2.5%) received the first dose of DTaP one month late (delayed DTaP). Overall, delayed DTaP was not associated with primary outcomes of food allergy (adjusted odds ratio (aOR) 0.77; 95% CI: 0.36-1.62, P = 0.49) or atopic sensitization (aOR: 0.66; 95% CI: 0.35-1.24, P = 0.19). Amongst secondary outcomes, delayed DTaP was associated with reduced eczema (aOR: 0.57; 95% CI: 0.34-0.97, P = 0.04) and reduced use of eczema medication (aOR: 0.45; 95% CI: 0.24-0.83, P = 0.01). CONCLUSIONS: There was no overall association between delayed DTaP and food allergy; however, children with delayed DTaP had less eczema and less use of eczema medication. Timing of routine infant immunizations may affect susceptibility to allergic disease.
Assuntos
Eczema/epidemiologia , Eczema/etiologia , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/etiologia , Vacinação/efeitos adversos , Vacinação/métodos , Estudos de Coortes , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Vias de Administração de Medicamentos , Feminino , Humanos , Lactente , Masculino , Razão de Chances , Avaliação de Resultados em Cuidados de Saúde , Vigilância da População , Risco , Fatores de Tempo , Vacinas/administração & dosagem , Vacinas/efeitos adversosRESUMO
BACKGROUND: Models that incorporate patterns of multiple cytokine responses to allergens, rather than individual cytokine production, may better predict sensitization and asthma. OBJECTIVE: To characterize the patterns of peripheral blood mononuclear cells' (PBMCs) cytokine responses to house dust mite (HDM) allergens among children from two population-based birth cohorts using machine learning techniques. METHODS: PBMCs collected at 8 years of age from the UK Manchester Asthma and Allergy Study (n = 268) and at 14 years of age from the Australian Raine Study (n = 1374) were cultured with HDM extract (10 µg/ml). Cytokine expression (IL-13, IL-5, IFN-γ, and IL10) was measured in the supernatant. Cytokine patterns were identified using a Gaussian mixture model clustering, and classification stability was assessed by bootstrapping. RESULTS: A six-class model indicated complex latent structure of cytokine expression. Based on the characteristics of each class, we designated them as follows: 'Nonresponders' (n = 905, 55%); 'IL-10 responders' (n = 49, 3%); 'IFN-γ and IL-13 medium responders' (n = 56, 3.4%); 'IL-13 medium responders' (n = 351, 21.4%); 'IL-5 and IL-13 medium responders' (n = 77, 4.7%); and 'IL-13 and IL-5 high responders' (n = 204, 12.4%). 'IL-13 and IL-5 high responders' were at much higher risk of HDM sensitization and asthma compared to all other classes, with 88% of children assigned to this class being sensitized and 28.5% having asthma. CONCLUSION: Using model-based clustering, we identified several distinct patterns of cytokine response to HDM and observed interplay between cytokine expression level, cytokine patterns (especially IL-13 and IL-5), and clinical outcomes. 'IL-13 and IL-5 high responders' class was strongly associated with HDM sensitization. However, among HDM-sensitized children, one-third showed no PBMC response to HDM, and the majority of HDM-sensitized children did not have asthma or wheeze. Our findings suggest that positive HDM 'allergy tests' and asthma are associated with a broad range of immunophenotypes, which may have important implications for the use of cytokine-targeted treatment approaches.
Assuntos
Citocinas/metabolismo , Hipersensibilidade/epidemiologia , Hipersensibilidade/metabolismo , Alérgenos/imunologia , Antígenos de Dermatophagoides , Austrália/epidemiologia , Criança , Estudos de Coortes , Feminino , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Avaliação de Resultados da Assistência ao Paciente , Vigilância em Saúde PúblicaRESUMO
This genome-wide association study (GWAS) utilises data from the Western Australian Pregnancy Cohort (Raine) Study for 25-hydroxyvitamin D (25(OH)D) levels measured in blood collected at age 6 years (n=673) and at age 14 years (n=1140). Replication of significantly associated genes from previous GWASs was found for both ages. Genome-wide significant associations were found both at age 6 and 14 with single nucleotide polymorphisms (SNPs) on chromosome 11p15 in PDE3B/CYP2R1 (age 6: rs1007392, P=3.9 × 10(-8); age14: rs11023332, P=2.2 × 10(-10)) and on chromosome 4q13 in GC (age 6: rs17467825, P=4.2 × 10(-9); age14: rs1155563; P=3.9 × 10(-9)). In addition, a novel association was observed at age 6 with SNPs on chromosome 7p15 near NPY (age 6: rs156299, P=1.3 × 10(-6)) that could be of functional interest in highlighting alternative pathways for vitamin D metabolism in this age group and merits further analysis in other cohort studies.
Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Cromossomos Humanos Par 11/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue , Adolescente , Criança , Cromossomos Humanos Par 7/genética , Estudos de Coortes , Família 2 do Citocromo P450 , Replicação do DNA/genética , Feminino , Seguimentos , Frequência do Gene , Genótipo , Humanos , Masculino , Neuropeptídeo Y/genética , Gravidez , Transdução de Sinais/genética , Austrália OcidentalRESUMO
Human leukocyte antigen (HLA)-G is upregulated on the bronchial epithelium of asthma patients and genetic polymorphism affecting expression of HLA-G has been reported to influence susceptibility to asthma. As the NK cell receptor KIR2DL4 has been reported to induce interferon gamma (IFNγ) secretion when ligated with HLA-G, we postulated that the 9A/10A genetic polymorphism of KIR2DL4 which influences receptor structure may influence susceptibility to asthma. KIR2DL4 genotypes were determined in two cohorts of children (n = 219 and n = 1356) in whom total serum IgE, allergen-specific IgE, atopy, bronchial reactivity and asthma symptoms had been studied between birth and 14 years. No reproducible associations with KIR2DL4 genotype were identified, leading us to conclude that the KIR2DL4 9A/10A polymorphism has no influence on susceptibility to asthma.
Assuntos
Asma/genética , Hiper-Reatividade Brônquica/genética , Antígenos HLA-G/genética , Polimorfismo Genético , Receptores KIR2DL4/genética , Adolescente , Asma/sangue , Asma/imunologia , Asma/patologia , Hiper-Reatividade Brônquica/sangue , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Criança , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Antígenos HLA-G/imunologia , Humanos , Imunoglobulina E/sangue , Lactente , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Estudos Longitudinais , Masculino , Receptores KIR2DL4/imunologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologiaRESUMO
Severe viral respiratory illnesses and atopy are risk factors for childhood wheezing and asthma. The aim of this study was to explore associations between severe respiratory infections and atopy in early childhood with wheeze and asthma persisting into later childhood. 147 children at high atopic risk were followed from birth to age 10 yrs. Data on all respiratory infections occurring in infancy were collected prospectively and viral aetiology ascertained. Atopy was measured by skin prick tests at 6 months, and 2 and 5 yrs. History of wheeze and doctor-diagnosed eczema and asthma was collected regularly until 10 yrs of age. At 10 yrs, 60% of the cohort was atopic, 25.9% had current eczema, 18.4% current asthma and 20.4% persistent wheeze. 35.8% experienced at least one lower respiratory infection (LRI) associated with fever and/or wheeze in first year of life. Children who had wheezy or, in particular, febrile LRI in infancy and were atopic by 2 yrs, were significantly more likely to have persistent wheeze (RR 3.51, 95% CI 1.83-6.70; p<0.001) and current asthma (RR 4.92, 95% CI 2.59-9.36; p<0.001) at 10 yrs. Severe viral respiratory infections in infancy and early atopy are risk factors for persistent wheeze and asthma. The strongest marker of the asthmatogenic potential of early life infections was concurrent fever. The occurrence of fever during respiratory illnesses is an important marker of risk for wheeze and asthma later in childhood, suggesting it should be measured in prospective studies of asthma aetiology.
Assuntos
Asma/epidemiologia , Febre/epidemiologia , Hipersensibilidade Imediata/epidemiologia , Pneumonia/epidemiologia , Infecções Respiratórias/epidemiologia , Criança , Pré-Escolar , Conjuntivite Alérgica/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Valor Preditivo dos Testes , Prevalência , Sons Respiratórios/etiologia , Rinite Alérgica Perene/epidemiologia , Rinite Alérgica Sazonal/epidemiologia , Fatores de Risco , Índice de Gravidade de Doença , Viroses/epidemiologiaRESUMO
BACKGROUND: Presymptomatic immaturity in neonatal T-cell function is a consistent antecedent of allergic disease, including reduced responsiveness to polyclonal activation. METHODS: To elucidate the underlying mechanisms, we examined for differences in T-cell gene expression in longitudinal samples collected at birth and at 1 year of age in children with (n = 30) and without IgE-mediated food allergy (n = 30). We employed a low-level soluble anti-CD3 stimulus to activate the T-cell receptor (TCR) and surveyed gene expression by DNA microarray in purified CD4(+) T-cells. Allergen-specific responses were assessed in parallel functional studies. RESULTS: At birth, the allergic group showed a reduced number of genes up regulated in response to anti-CD3 treatment on the microarray and a reduced lympho proliferative capacity, suggesting clear differences in T-cell signalling pathways. Polymerase chain reaction (PCR) validation of candidate genes confirmed significantly lower expression of a number of genes in the allergic group including RELB, NFKB2, LIF and FAS. By 12 months of age, there were marked changes in the anti-CD3 response in all infants, culminating in upregulation of cytokine genes (IL-5, IL-13, IL-17 and IL-22). Neonatal differences were no longer apparent. Instead, the allergic group, all symptomatic by this age, showed differential expression of T-cell lineage pathways including GATA-3, MAL and FcER1 in unstimulated T-cells. Allergen stimulation induced significantly higher cytokines production (IL-5, IL-13 and IFNγ) in the allergic group. CONCLUSION: Although transient, suboptimal neonatal T-cell activation pathways that signal through the NF-κB complex may affect the developmental transition of T-cell phenotypes in the periphery shortly after birth and may increase the risk of food allergy.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/imunologia , Regulação da Expressão Gênica , Ativação Linfocitária/genética , Alérgenos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Análise por Conglomerados , Citocinas/biossíntese , Citocinas/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de SinaisAssuntos
Asma , Extratos Celulares , Adjuvantes Imunológicos , Animais , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Vitamin D has been linked in some studies with atopy- and asthma-associated phenotypes in children with established disease, but its role in disease inception at the community level is less clear. The aim of the present study was to investigate associations between vitamin D status and biological signatures indicative of allergy and asthma development in children aged 6 and 14 years in Perth, WA, Australia (latitude 32° S). Serum vitamin D was assayed in 989 6-yr-olds and 1,380 14-yr-olds from an unselected community birth cohort; 689 subjects were assessed at both ages. Vitamin D levels were assessed as a risk modifier for respiratory and allergic outcomes at both ages, using previously ascertained phenotypic data. The predictive value of vitamin D levels at age 6 yrs for development of clinical phenotypes at age 14 yrs was also examined. Serum vitamin D levels in children of both ages were negatively associated with concurrent allergic phenotypes; sex stratification revealed that this association was restricted mainly to males. Furthermore, vitamin D levels at age 6 yrs were significant predictors of subsequent atopy/asthma-associated phenotypes at age 14 yrs. In an unselected community setting, children (particularly males) with inadequate vitamin D are at increased risk of developing atopy, and subsequently bronchial hyperresponsiveness (BHR) and asthma. In a large unselected cohort, males with inadequate vitamin D at 6 and 14 yrs of age had increased atopy and BHR. Low vitamin D at age 6 yrs was a predictor of atopy and asthma at 14 yrs of age.
Assuntos
Asma/sangue , Vitamina D/sangue , Adolescente , Alérgenos/sangue , Animais , Asma/fisiopatologia , Hiper-Reatividade Brônquica/sangue , Criança , Feminino , Humanos , Hipersensibilidade/sangue , Imunoglobulina E/sangue , Estudos Longitudinais , Masculino , Valor Preditivo dos Testes , Prevalência , Pyroglyphidae , Testes de Função Respiratória , Sons Respiratórios/fisiopatologia , Rinite/sangue , Fatores de Risco , Fatores Sexuais , Austrália Ocidental/epidemiologiaRESUMO
Persistent allergic diseases exemplified by atopic asthma frequently begin during very early life. Epidemiological findings indicate that progression from allergic sensitization to atopic asthma occurs most frequently when atopy is accompanied by early respiratory viral infections. The underlying mechanism appears to involve recruitment of atopy-associated effector mechanisms into the host response to the virus. This has the dual effect of antagonising anti-viral immunity and amplifying inflammation in the infected airway mucosa, driving asthma pathogenesis. Immune responses underlying the allergic state are uniquely plastic during childhood. Alleviating specific allergy during this period may reduce risk of subsequent asthma development.
Assuntos
Hipersensibilidade/etiologia , Hipersensibilidade/imunologia , Viroses/complicações , Viroses/imunologia , Asma/etiologia , Asma/imunologia , Asma/prevenção & controle , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Humanos , Mucosa Respiratória/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
BACKGROUND: It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine whether cord blood VDD is associated with FS and whether such association can be modified by genetic variants in a prospective birth cohort. METHODS: This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D < 11 ng/ml, and FS as specific IgE ≥ 0.35 kUA/l to any of eight common food allergens in early childhood. We genotyped potentially functional single-nucleotide polymorphisms (SNPs) in 11 genes known to be involved in regulating IgE and 25(OH)D concentrations. Logistic regressions were used to test the effects of VDD on FS individually and jointly with SNPs. RESULTS: Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD (p(interaction) = 0.003, p(FDR) = 0.10) was found: VDD increased the risk of FS among children carrying CC/CT genotypes (OR = 1.79, 95%CI: 1.15-2.77). Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident (p(interaction) = 9 × 10(-6) ). CONCLUSIONS: Our data demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene-vitamin D interaction on FS.
Assuntos
Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/epidemiologia , Vitamina D/sangue , Adulto , Pré-Escolar , Estudos de Coortes , Feminino , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/etiologia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Fatores de Risco , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/genéticaRESUMO
gammadelta T cells downregulate airways responsiveness to allergen challenge, possibly by controlling the 'repair' response of the airway epithelium to alphabeta T cell-mediated damage (pages 1150-1156).
Assuntos
Asma/imunologia , Hipersensibilidade Imediata/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Sistema Respiratório/imunologia , Modelos Imunológicos , Mucosa/citologia , Mucosa/imunologia , Sistema Respiratório/citologiaRESUMO
Resident pulmonary alveolar macrophages (PAM) play an important role in the maintenance of immunological homeostasis in the lung via downmodulation of local T cell responses in the steady state. The present study demonstrates that this pathway for T cell suppression is reversible via granulocyte/macrophage colony-stimulating factor (GM-CSF). Thus, freshly isolated PAM strongly inhibit mitogen-induced T cell proliferation, and pretreatment of the PAM with cytokine-rich lung-conditioned medium (LCM) generated by exposure of lung to bacterial lipopolysaccharide (LPS) abrogated this suppressive activity. LCM from lungs of normal and athymic nude mice exhibited identical activity. Moreover, the PAM-modulating activity of LCM was inhibited by blocking antibody specific for GM-CSF, and the activity of LCM could be reproduced by recombinant GM-CSF. This suggests that secretion of GM-CSF by mesenchymal cells and/or macrophages under stimulation from agents such as LPS provides a potential mechanism for upregulation of local T cell responsiveness during acute inflammation. In addition, experiments with a range of cytokines indicated that interleukin 4, transforming growth factor beta 1 and tumor necrosis factor alpha (TNF-alpha) exhibited weaker (but significant) modulatory effects on PAM, and (in the case of TNF-alpha) amplified the effects of GM-CSF.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Animais , Meios de Cultivo Condicionados , Feminino , Pulmão/fisiologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
The immunological basis for atopy is currently ascribed to an inherent bias in the CD4+ T cell response to nonreplicating antigens presented at mucosal surfaces, resulting in dominance of the T helper 2 (Th2) interleukin 4 (IL-4)-producing phenotype, which favors IgE production. In contrast, the "normal" response to such antigens involves a predominance of interferon gamma (IFN-gamma)-producing Th1 clones. This difference has been suggested to be the result of active selection in atopics for Th2 (and hence against Th1) clones at the time of initial antigen presentation. In the study below, we demonstrate that the natural immune response to inhaled protein antigens, particularly in animals expressing the low immunoglobulin E (IgE) responder phenotype, includes a major histocompatibility complex (MHC) class I-restricted CD8+ T cell component, the appearance of which is associated with active suppression of IgE antibody production. Thus, continued exposure of rats to aerosolized ovalbumin (OVA) antigen elicits a transient IgE response, that is terminated by the onset of a state of apparent "tolerance" to further challenge, and this tolerant state is transferable to naive animals with CD8+ T cells. Kinetic studies on in vitro T cell reactivity in these aerosol-exposed rats demonstrated biphasic CD4+ Th2 responses which terminated, together with IgE antibody production, and coincident with the appearance of MHC class I-restricted OVA-specific IFN-gamma-producing CD8+ T cells. However, the latter were not autonomous in vitro and required a source of exogenous IL-2 for initial activation, which in CD(8+)-enriched splenocyte cultures could be provided by small numbers of contaminating OVA-specific CD4+ T cells. This represents the first formal evidence for the induction of an MHC class I-restricted T cell response to natural mucosal exposure to an inert protein antigen, and is consistent with a growing literature demonstrating sensitization of MHC class I-restricted CD8+ T cells by deliberate immunization with soluble proteins. We suggest that crossregulation of MHC class II-restricted CD4+ T cells via cytokine signals generated in parallel CD8+ T cell responses represents a covert and potentially important selection pressure that can shape the nature of host responses to nonreplicating antigens presented at mucosal surfaces.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoglobulina E/imunologia , Ovalbumina/imunologia , Proteínas/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Aerossóis , Animais , Antígenos CD8/análise , Imunização , Imunização Passiva , Imunoglobulina G/imunologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária , Complexo Principal de Histocompatibilidade , Ovalbumina/química , Proteínas/química , Ratos , Ratos Endogâmicos , SolubilidadeRESUMO
A new assay system is described for the enumeration of antigen-specific IgE immunoglobulin-secreting cells (ISC) based on an enzyme-linked immunoabsorbent assay. Using this technique to monitor the organ distribution of OVA-specific ISC after primary immunization of rats, approximately 12,000 specific IgE ISC were detected at the peak of the response in the draining lymph nodes compared with 117,000 IgG ISC; the splenic anti-OVA response was restricted to the IgM class. Using plates precoated with anti-rat IgE instead of antigen, total IgE ISC were enumerated in normal and helminth-parasitized rats. The assay system detected up to 5 X 10(5) IgE ISC in mesenteric lymph nodes from parasitized animals compared with less than 50 in controls.
Assuntos
Imunoglobulina E/biossíntese , Linfonodos/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Infecções por Uncinaria/imunologia , Imunização , Masculino , Nippostrongylus , Ovalbumina/imunologia , Ratos , Distribuição Tecidual , Ensaio de Placa ViralRESUMO
Collagenase digestion of tissue slices from perfused, lavaged SPF rat lung released approximately 10(8) viable mononuclear cells per gram tissue, which comprised 35% T lymphocytes and up to 26% macrophages. A subset of these cells that were Ia+, surface Ig-, nonadherent, FcR- and of ultra low density (putative dendritic cells [DC]), presented protein antigen to immune T cells in vitro, and this function was inhibited by the presence of low numbers of endogenous adherent, FcR+ cells (putative macrophages). APCs were also identified in digests from tracheal epithelium, and were shown to bind antigen in immunogenic form as a result of natural (inhalation) exposure in vivo. Immunoperoxidase staining of frozen sections revealed populations of strongly Ia+ cells with prominent DC-like morphology within the alveolar septal walls and the tracheal epithelium; in both areas, they were closely associated with pleiomorphic cells that expressed macrophage surface markers. We accordingly postulate that interactions between Ia+ antigen-presenting DCs and endogenous tissue macrophages play an important role in regulating T cell activity in the respiratory tract.
Assuntos
Células Dendríticas/classificação , Antígenos de Histocompatibilidade Classe II/imunologia , Macrófagos/classificação , Alvéolos Pulmonares/citologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Células Dendríticas/imunologia , Células Epiteliais , Feminino , Imuno-Histoquímica , Macrófagos/imunologia , Ovalbumina/imunologia , Alvéolos Pulmonares/imunologia , Ratos , Ratos Endogâmicos , Traqueia/citologiaRESUMO
Immunohistochemical analysis of challenge sites such as skin and the peritoneal cavity has identified neutrophils as virtually the sole cellular participants in acute bacterial inflammation, peak influx occurring 24-48 h in advance of mononuclear cell populations associated with adaptive immunity. This study challenges the general applicability of this paradigm. We demonstrate here that the earliest detectable cellular response after inhalation of Moraxella catarrhalis organisms is the recruitment of putative class II major histocompatibility complex-bearing dendritic cell (DC) precursors into the airway epithelium, the initial wave arriving in advance of the neutrophil influx. Unlike the neutrophils which rapidly transit into the airway lumen, the DC precursors remain within the epithelium during the acute inflammatory response where they differentiate, and develop the dendriform morphology typical of resident DC found in the normal epithelium. During the ensuing 48-h period, these cells then migrate to the regional lymph nodes. No comparable DC response was observed after epidermal or intraperitoneal challenge, and it may be that mucosal surfaces are unique in their requirement for rapid DC responses during acute inflammation. We hypothesize that the role of the DC influx during acute inflammation may be surveillance for opportunistic viruses, and that this covert protective mechanism is operative at a restricted number of mucosal tissue sites.
Assuntos
Células Dendríticas/imunologia , Inflamação/imunologia , Moraxella catarrhalis/imunologia , Mucosa Nasal/imunologia , Animais , Movimento Celular , Células Dendríticas/citologia , Vida Livre de Germes , Antígenos de Histocompatibilidade Classe II/imunologia , Mucosa Nasal/citologia , RatosRESUMO
Conventional immunohistochemical analysis of airway intraepithelial class II major histocompatibility complex (Ia) expression demonstrates a morphologically heterogeneous pattern of staining, suggestive of the presence of a mixed population of endogenous antigen presenting cells. Employing a novel tissue sectioning technique in conjunction with optimal surface antigen fixation, we now demonstrate that virtually all intraepithelial Ia staining throughout the respiratory tree in the normal rat, can be accounted for by a network of cells with classical dendritic cell (DC) morphology. The density of DC varies from 600-800 per mm2 epithelial surface in the large airways, to 75 per mm2 in the epithelium of the small airways of the peripheral lung. All the airway DC costain for CD4, with low-moderate expression of a variety of other leukocyte surface markers. Both chronic (eosinophilic) inflammation and acute (neutrophilic) inflammation, caused respectively by inhalation of chemical irritants in dust or aerosolised bacterial lipopolysaccharide (LPS), are shown to be accompanied by increased intraepithelial DC density in the large airways (in the order of 50%) and up to threefold increased expression of activation markers, including the beta chain of CD11/18. The kinetics of the changes in the DC network in response to LPS mirrored those of the transient neutrophil influx, suggesting that airway intraepithelial DC constitute a dynamic population which is rapidly upregulated in response to local inflammation. These findings have important theoretical implications for research on T cell activation in the context of allergic and infectious diseases in the respiratory tract.
Assuntos
Antígenos de Superfície/análise , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe II/análise , Traqueia/imunologia , Animais , Anticorpos Monoclonais , Células Epiteliais , Epitélio/imunologia , Epitélio/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos WF , Traqueia/citologiaRESUMO
The relative inefficiency of respiratory mucosal immune function during infancy is generally attributed to the immaturity of the neonatal T cell system. However, immune competence in the adult lung has recently been shown to be closely linked to the functional capacity of local networks of intraepithelial dendritic cells (DC). This study examines the density and distribution of these DC throughout the neonatal respiratory tract in rats, focusing particularly on microenvironmental regulation of their class II major histocompatibility complex (MHC) (Ia) expression. In animals housed under dust-controlled conditions, airway epithelial and alveolar Ia+ DC detectable by immunostaining with the monoclonal antibody (mAb) Ox6 are usually not seen until day 2-3 after birth, and adult-equivalent staining patterns are not observed until after weaning. In contrast, the mAb Ox62 detects large numbers of DC in fetal, infant, and adult rat airway epithelium. Costaining of these Ox62+ DC with Ox6 is rare in the neonate and increases progressively throughout infancy, and by weaning Ia+ DC comprised, on average, 65% of the overall intraepithelial DC population. In infant rats, Ia+ DC are observed first at the base of the nasal turbinates, sites of maximum exposure to inhaled particulates, suggesting that their maturation is driven in part by inflammatory stimuli. Consistent with this suggestion, densitometric analysis of Ia staining intensity of individual DC demonstrates that by 2-3 d after birth, Ia expression by nasal epithelial DC was comparable with that of Iahigh epidermal Langerhans cells in adjacent facial skin, at a time when expression by tracheal epithelial DC was 7-10-fold lower. Additionally, the rate of postnatal appearance of Iahigh DC in the airway epithelium was increased by administration of interferon gamma, and decreased by exposure of infant rats to aerosolized steroid. These findings collectively suggest that Ia expression by neonatal respiratory tract DC is locally controlled and can be upregulated by mediators that are produced within the lung and airway epithelium in response to inhalation of proinflammatory stimuli. It was also noted that Ialow neonatal airway DC expressed adult equivalent levels of class I MHC, which suggests differences in capacity to prime for CD8(+)-dependent versus CD4(+)-dependent immunity to inhaled pathogens, during the early postnatal period.