RESUMO
BACKGROUND: The origins of asthma and allergic disease begin in early life for many individuals. It is vital to understand the factors and/or events leading to their development. METHODS: The Childhood Origins of Asthma project evaluated children at high risk for asthma to study the relationships among viral infections, environmental factors, immune dysregulation, genetic factors, and the development of atopic diseases. Consequently wheezing illnesses, viral respiratory pathogen identification, and in vitro cytokine response profiles were comprehensively evaluated from birth to 3 years of age, and associations of the observed phenotypes with genetic polymorphisms were investigated. RESULTS: For the entire cohort, cytokine responses did not develop according to a strict T helper cell 1 or T helper cell 2 polarization pattern during infancy. Increased cord blood mononuclear cell phytohemagglutin-induced interferon-gamma responses of mononuclear cells were associated with decreased numbers of moderate to severe viral infections during infancy, especially among subjects with the greatest exposure to other children. In support of the hygiene hypothesis, an increased frequency of viral infections in infancy resulted in increased mitogen-induced interferon-gamma responses at 1 year of age. First year wheezing illnesses caused by respiratory viral infection were the strongest predictor of subsequent third year wheezing. Also, genotypic variation interacting with environmental factors, including day care, was associated with clinical and immunologic phenotypes that may precede the development of asthma. CONCLUSIONS: Associations between clinical wheezing, viral identification, specific cytokine responses and genetic variation provide insight into the immunopathogenesis of childhood asthma and allergic diseases.
Assuntos
Asma/etiologia , Citocinas/metabolismo , Hipersensibilidade Imediata/etiologia , Infecções Respiratórias/complicações , Viroses/complicações , Animais , Asma/genética , Asma/imunologia , Criança , Pré-Escolar , Humanos , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Lactente , Recém-Nascido , Camundongos , Sons Respiratórios/etiologia , Sons Respiratórios/imunologia , Infecções Respiratórias/virologiaRESUMO
BACKGROUND: Viral infections are the major cause of acute wheezing illnesses in childhood. Variations in immunologic responses at birth may be determinants of the risk of acquiring these illnesses. OBJECTIVES: To determine the immunologic risk factors for virus-induced wheezing in high-risk infants. METHODS: The study involves 285 children with a parental history of asthma and/or respiratory allergies. Mononuclear cells obtained at birth (umbilical cord blood) and at 1 year of age were incubated with phytohemagglutinin, respiratory syncytial virus, or rhinovirus, and supernatants were analyzed for IL-5, IL-10, IL-13, and IFN-gamma. Nasal secretions obtained at well child visits and during respiratory illnesses were analyzed for common respiratory viruses. RESULTS: Respiratory syncytial virus-induced wheezing was associated with reduced phytohemagglutinin-induced IL-13 responses (medians, 213 vs 304 pg/mL; P = .026) from cord blood cells, and similar trends were found for wheezing in general. Furthermore, median IL-13 responses diminished by 28% in non-wheezing children by age 1 year, versus only 3% in wheezing children (P = .013). Children with > or =2 episodes of wheezing had lower phytohemagglutinin-induced IFN-gamma responses and were less likely to have rhinovirus-induced IFN-gamma responses at birth (P < .05). Finally, children with measurable cord blood IFN responses to respiratory syncytial virus were less likely to wheeze in their first year (odds ratio, 0.43 [0.23, 0.79]). CONCLUSION: In children with a family history of allergies and/or asthma, mononuclear cell phytohemagglutinin-induced IL-13 and virus-induced IFN-gamma responses at birth are indicative of the risk for wheezing in the first year of life.
Assuntos
Citocinas/biossíntese , Sons Respiratórios/etiologia , Viroses/imunologia , Resfriado Comum/imunologia , Humanos , Lactente , Recém-Nascido , Interferon gama/biossíntese , Interleucina-13/biossíntese , Fito-Hemaglutininas/farmacologia , Infecções por Vírus Respiratório Sincicial/imunologia , Fatores de RiscoRESUMO
Analogous to childhood-onset asthma in humans, rats may develop a chronic asthmalike phenotype, depending on their genetic background and the age at which they experience a viral airway injury. Brown Norway rats develop a postbronchiolitis asthmalike phenotype that may be prevented with supplements of interferon-gamma (IFN-gamma); we hypothesized that the normally resistant F344 rat strain would develop the asthmalike phenotype if the IFN-gamma response were suppressed during viral illness. Weanling F344 rats were pretreated with anti-IFN-gamma or control antibody, and inoculated with Sendai virus or vehicle. Anti-IFN-gamma treatment reduced lung IFN-gamma and increased IL-4 mRNA during the infection. Physiologic studies performed 8 wk later revealed premature airway closure (p = 0.03) and elevated specific pulmonary resistance (p < 0.01) in the postbronchiolitis anti-IFN-gamma group compared with noninfected controls and untreated postbronchiolitis rats. However, unlike the postbronchiolitis asthmalike phenotype in Brown Norway rats, bronchiolar inflammation and fibrosis were absent in the F344 rats. Lung elastic recoil and alveolar surface density also were unchanged compared with noninfected control rats. We conclude that there is an interactive effect of a weak IFN-gamma response and viral bronchiolitis at an early age that may result in persistent postbronchiolitis airway dysfunction. The presence of premature airway closure that is independent of airway wall inflammation or changes in lung elastic recoil suggests peripheral airway instability as a mechanism for the airway obstruction.
Assuntos
Anticorpos/imunologia , Asma/fisiopatologia , Bronquiolite/fisiopatologia , Interferon gama/imunologia , Resistência das Vias Respiratórias/fisiologia , Animais , Líquido da Lavagem Broncoalveolar/química , Doença Crônica , Humanos , Interferon gama/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Fatores de TempoRESUMO
After Sendai virus (SeV)-induced bronchiolitis as weanlings, BN, but not F344, rats develop a postbronchiolitis asthma-like phenotype, which can be prevented by supplemental interferon (IFN)-gamma treatment. We have shown that splenocytes from BN weanlings, compared with those from F344 weanlings, have a markedly reduced capacity for IFN-gamma production. We hypothesized that SeV-induced IFN-gamma production occurs via innate mechanisms that are attenuated in BN weanlings. Therefore, we investigated potential mechanisms of SeV-induced IFN-gamma production in BN and F344 weanlings. SeV-stimulated splenocytes secreted the IFN-gamma-inducing cytokines, interleukin (IL)-12 and IL-18. BN splenocytes produced significantly less IL-12 (P = 0.001) and IL-18 (P < 0.001) than did F344 splenocytes. Depletion studies demonstrated that natural killer cells were the primary source of SeV-induced IFN-gamma production. Anti-IL-12 antibody, IL-12 p40 homodimer, and IL-18 binding protein each inhibited SeV-induced IFN-gamma production by 82-94%, and the combination of IL-12 p40 homodimer and IL-18 binding protein abolished SeV-induced IFN-gamma production, demonstrating synergism between IL-12 and IL-18. Therefore, SeV-induced IFN-gamma production occurred via innate IL-12-, IL-18-, and natural killer cell-dependent mechanisms, which were attenuated in BN weanlings. Attenuation of innate IFN-gamma-producing responses to SeV in BN weanlings may be a critical factor in their susceptibility to postbronchiolitis chronic airway dysfunction.
Assuntos
Bronquiolite Viral/metabolismo , Interferon gama/metabolismo , Infecções por Respirovirus/metabolismo , Vírus Sendai/metabolismo , Baço/citologia , Animais , Células Cultivadas , Humanos , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Baço/metabolismo , Baço/virologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
After viral bronchiolitis at an early age, a chronic asthma-like syndrome develops in BN, but not F344, rats. We hypothesized that the BN strain is less effective at clearing virus from the involved tissues. Weanling BN and F344 rats were inoculated with Sendai virus, and lung and peribronchial lymph nodes were harvested from each strain at 5 to 84 days after infection; control tissues were obtained from noninfected rats. Lung viral titers were similar for the 2 strains, with no infectious virus detectable by day 10. However, viral RNA was detected consistently by means of RT-PCR analyses in lungs and lymph nodes of both strains from days 10 to 27 and was still present at day 84 in some of the tissues from each strain. In contrast, there were strain-related differences in immune responses because IL-13 levels remained increased in the lung secretions of BN rats at 4 weeks after inoculation. Thus although Sendai virus could persist for at least 3 months after an acute infection in rats, this did not differ with strain. The persistent increase in IL-13 suggests instead that the strain-related variability in virus-associated airway pathology might be determined by the host response to infection rather than by the intensity or duration of infection.
Assuntos
Bronquiolite Viral/complicações , RNA Viral/análise , Transtornos Respiratórios/etiologia , Infecções por Respirovirus/genética , Vírus Sendai/genética , Animais , Bronquiolite Viral/virologia , Suscetibilidade a Doenças , Masculino , Ratos , Ratos Endogâmicos BN/genética , Ratos Endogâmicos F344/genética , Ensaio de Placa Viral , Latência ViralRESUMO
Daycare attendance and siblings are associated with viral-induced wheezing in children. Preexisting immunologic factors may influence the expression of viral infections in infancy, and in turn, recurrent infections may influence the development of immune responses. A total of 285 children were enrolled in the Childhood Origins of Asthma Project at birth and followed for at least 1 year. Cord blood and 1-year mononuclear cells were stimulated with phytohemagglutinin, and cytokine-response profiles were measured by enzyme-linked immunosorbent assay. Nasal lavage was performed for moderate to severe respiratory illnesses. Daycare attendance and/or siblings significantly increased the likelihood of contracting respiratory syncytial virus (1.5-1.6-fold increase) and rhinovirus (1.8-2.1-fold increase), and increased the risk of rhinovirus-induced wheezing (14-18% vs. 2%, p = 0.011). Cord blood IFN-gamma responses were inversely related to the frequency of viral respiratory infections (r(s) = -0.11, p = 0.05), and more significant for subjects with high exposure to other children (r(s) = -0.27, p = 0.028). The interval change in infantile IFN-gamma responses correlated positively with the frequency of viral infections in infancy (r(s) = 0.12, p = 0.047). These data suggest that neonatal IFN-gamma responses may influence antiviral activity, or may represent a marker of antiviral immunity maturation. Conversely, the frequency of viral infections in infancy can influence IFN-gamma responses.
Assuntos
Creches/estatística & dados numéricos , Citocinas/sangue , Monitoramento Ambiental/estatística & dados numéricos , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/imunologia , Viroses/epidemiologia , Viroses/imunologia , Desenvolvimento Infantil , Estudos de Coortes , Monitoramento Epidemiológico , Sangue Fetal/imunologia , Humanos , Lactente , Cuidado do Lactente/estatística & dados numéricos , Recém-Nascido , Cavidade Nasal/virologia , Pediatria/estatística & dados numéricos , Estudos Prospectivos , Sons Respiratórios , Infecções Respiratórias/virologia , Irmãos , Irrigação Terapêutica , Viroses/virologia , Wisconsin/epidemiologiaRESUMO
BACKGROUND: Exposure to furred pets might confer protection against the development of allergic sensitization through a mechanism that is incompletely understood. OBJECTIVE: The objective of this study was to determine the effects of pet exposure and genotype on immunologic development and the incidence of atopic markers and diseases in the first year of life. METHODS: Pet exposure in the home was compared with cytokine secretion patterns (mitogen-stimulated mononuclear cells at birth and age 1 year) and indicators of atopy (allergen-specific and total IgE, eosinophilia, food allergy, atopic dermatitis) in 285 infants. Interactions with genotype at the CD14 locus were also evaluated in the data analyses. RESULTS: Exposure to dogs was associated with reduced allergen sensitization (19% vs 33%, P =.020) and atopic dermatitis (30% vs 51%, P <.001). The risk for atopic dermatitis was further influenced by genotype at the CD14 locus (P =.006), even after adjusting for exposure to dogs (P =.003). Furthermore, infants with the genotype -159TT were less likely to develop atopic dermatitis if they were exposed to a dog (5% vs 43%, P =.04). Last, dog exposure was associated with increased IL-10 (117 vs 79 pg/mL, P =.002) and IL-13 (280 vs 226 pg/mL, P =.013) responses at age 1 year. CONCLUSIONS: Having a dog in infancy is associated with higher IL-10 and IL-13 cytokine secretion profiles and reduced allergic sensitization and atopic dermatitis. These findings suggest that postnatal exposure to dogs can influence immune development in a genotype-specific fashion and thereby attenuate the development of atopy in at-risk children.
Assuntos
Envelhecimento/imunologia , Alérgenos/efeitos adversos , Animais Domésticos , Citocinas/biossíntese , Hipersensibilidade Imediata/epidemiologia , Receptores de Lipopolissacarídeos/genética , Adulto , Animais , Gatos , Dermatite Atópica/epidemiologia , Dermatite Atópica/etiologia , Cães , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/etiologia , Genótipo , Humanos , Hipersensibilidade Imediata/etiologia , Lactente , Recém-Nascido , Interleucina-10/biossíntese , Interleucina-13/biossíntese , Fatores de RiscoRESUMO
BACKGROUND: Allergic diseases have been linked to abnormal patterns of immune development, and this has stimulated efforts to define the precise patterns of cytokine dysregulation that are associated with specific atopic phenotypes. OBJECTIVE: Cytokine-response profiles were prospectively analyzed over the first year of life and compared with the clinical and immunologic expressions of atopy. METHODS: Umbilical cord and 1-year PBMCs were obtained from 285 subjects from allergic families. PHA-stimulated cytokine-response profiles (IL-5, IL-10, IL-13, and IFN-gamma) were compared with blood eosinophil counts and total and specific IgE levels (dust mites, cat, egg, Alternaria species, peanut, milk, and dog) at age 1 year and at the development of atopic dermatitis and food allergy. RESULTS: For the cohort as a whole, cytokine responses did not evolve according to a strict TH1 or TH2 polarization pattern. PHA-stimulated cord blood cells secreted low levels of IL-5 (2.1 pg/mL), moderate levels of IFN-gamma (57.4 pg/mL), and greater amounts of IL-13 (281.8 pg/mL). From birth to 1 year, IL-5 responses dramatically increased, whereas IL-13 and IFN-gamma responses significantly decreased. Reduced cord blood secretion of IL-10 and IFN-gamma was associated with subsequent sensitization to egg. In addition, there was evidence of TH2 polarization (increased IL-5 and IL-13 levels) associated with blood eosinophilia and increased total IgE levels by age 1 year. CONCLUSION: These findings demonstrate that cytokine responses change markedly during the first year of life and provide further evidence of a close relationship between TH2 skewing of immune responses and the incidence of atopic manifestations in children.