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dc.contributor.supervisor HayGlass, Kent T. (Immunology) en
dc.contributor.author Douville, Renee Nicole
dc.date.accessioned 2007-09-11T19:03:31Z
dc.date.available 2007-09-11T19:03:31Z
dc.date.issued 2007-09-11T19:03:31Z
dc.identifier.citation Douville, Renee, et al. (2006). The Journal of Immunology, 176: 5848–5855. en
dc.identifier.citation Douville, Renee, et al. (2007). Biochemistry and Cell Biology, Apr;85(2):252-8. en
dc.identifier.uri http://hdl.handle.net/1993/2807
dc.description.abstract Respiratory virus infections are associated with asthma pathogenesis and exacerbations in children and adults. Unfortunately, it remains largely unknown whether innate and adaptive T cell anti-viral immunity differs in allergic disease versus health. Here, we established a short-term primary cell culture system using human peripheral blood mononuclear cells (PBMC) optimized for measuring immune responses to reovirus, respiratory syncytial virus (RSV) and metapneumovirus (MPV) based on virus-specific cytokine and chemokine production. The prevalence and intensity of innate and adaptive responses in children and adult populations was addressed. Using this in vitro model of human anti-viral immunity, we tested our global hypothesis that asthmatics mount anti-viral cytokine responses to respiratory viruses that differ from those of healthy individuals. MPV and RSV, although both ubiquitous and leading to very high levels of infection, seroconversion and clinically similar presentation in the population, evoke distinct innate and adaptive T cell-dependent cytokine responses. Reovirus induced exceptionally strong IFN recall responses concomitant with intense IL-10 production, which were independent of viral replication in PBMC. Surprisingly, despite Type 1 cytokine production dominated adaptive immune responses in both asthmatic and non-asthmatic individuals, asthmatics exhibited significantly stronger pro-inflammatory IFNγ and IL-10 production towards virus stimulation than non-asthmatic children and adults. Moreover, children with current AHR, regardless of asthmatic status, exhibit a greater frequency and intensity of IFNγ responses towards pneumoviruses than do non-AHR counterparts. Conversely, expression of chemokine CCL5 was substantially weaker in asthmatics, and was further decreased in children with AHR and familial history of asthma. This pattern of enhanced pro-inflammatory and deficient anti-viral CCL5 responses towards pneumoviruses in children with markers of symptomatic asthma or AHR may underlie the enhanced sensitivity of these children to experience breathing difficulties following infection with respiratory viruses. Furthermore, we have clearly demonstrated a gene by environment interaction, whereby ETS exposure in children with familial asthma results in suppressed anti-viral IFNγ and IL-10 production. Therefore, we have attempted to determine whether genetic variation affects the intermediate phenotype of anti-viral immunity, in the population and dependent on clinical status. In summary, we have demonstrated that asthma, childhood exposures and genetics shape anti-viral cytokine responses in human. These findings have a substantial impact for physicians deciding the contextually appropriate treatment for asthma symptoms in their patients and could have implications for experimentation relating to mechanisms of disease, clinical practice and development of appropriate therapeutics. en
dc.format.extent 4558796 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Immunology en
dc.subject Virus en
dc.subject Immunity en
dc.subject Cytokine en
dc.subject Genetics en
dc.subject Human en
dc.subject Asthma en
dc.subject RSV en
dc.subject MPV en
dc.subject Reovirus en
dc.subject PBMC en
dc.subject ETS en
dc.title Asthma, childhood exposures and genetics shape anti-viral cytokine responses in humans en
dc.degree.discipline Immunology en
dc.contributor.examiningcommittee Becker, Allan (Pediatrics & Child Health) Coombs, Kevin (Medical Microbiology) Hegele, Richard (Pathology and Laboratory Medicine, University of British Columbia) Soussi-Gounni, Abdelilah (Immunology) Yang, Xi (Medical Microbiology, Immunology) en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note October 2007 en


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