Kiva Adler

Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life

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.

Relationships among specific viral pathogens, virus-induced interleukin-8, and respiratory symptoms in infancy.

Both virus‐mediated damage to airway tissues and induction of pro‐inflammatory cytokines such as interleukin‐8 (IL‐8) could contribute to symptom severity during viral respiratory infections in children. To test the hypothesis that IL‐8 contributes to the pathogenesis of respiratory symptoms during naturally acquired respiratory viral infections in children, nasal wash samples collected from infants with acute viral infections (n = 198) or from healthy uninfected infants (n = 31) were analysed for IL‐8. Nasal wash IL‐8 was positively related to age in uninfected children (rs = 0.36, p < 0.05). Respiratory syncytial virus (RSV) infection caused more severe respiratory symptoms compared to infections with influenza A, parainfluenza viruses, or rhinoviruses. In addition, RSV, parainfluenza and rhinovirus infections increased levels of IL‐8 in nasal lavage fluid, and there were some differences in the ability of the viruses to induce IL‐8 production (RSV>influenza, p < 0.05). Finally, there were significant correlations between nasal wash IL‐8 levels and symptom scores during infections with rhinovirus (rs = 0.56, p < 0.001) or influenza A (rs = 0.45, p < 0.05), but not with parainfluenza virus or RSV. These findings provide evidence of a close relationship between the generation of IL‐8 and symptoms during acute community‐acquired infections with rhinovirus or influenza A. In contrast, for RSV and parainfluenza infections, factors in addition to IL‐8 production appear to contribute to the generation of clinical symptoms.

Viral infections, cytokine dysregulation and the origins of childhood asthma and allergic diseases.

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-γ 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-γ 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.