242:
Associations Between Asthma Severity and Responsiveness to Th2- and Th17-derived Cytokines in Pediatric Asthmatics
Saturday, March 3, 2018
South Hall A2 (Convention Center)
Jaclyn W. McAlees, Ph.D., Theresa Baker, M.S., Sara L. Hall, Ph.D., Emily Kim, Christopher G. McKnight, MD, Andrew Warren Lindsley, MD PhD, Richard Thomas Strait, MD, Xue Zhang, Ph.D., Jocelyn M Biagini Myers, Ph.D., Melinda Butsch Kovacic, Ph.D., Ian Paul Lewkowich, PhD
RATIONALE: Mild and moderate allergic asthma are characterized by airway eosinophilia, airway hyperresponsiveness and a maladaptive Th2 response to aeroallergens, which is typically well controlled with steroids. Severe steroid refractory asthma is often associated with neutrophilic inflammation, elevated Th17 cell numbers and IL-17A. A mouse model of allergen-driven severe asthma supports an association between Th17 responses and severe disease, and demonstrate that severely asthmatic animals have increased production of Th17 cytokines and responsiveness to IL-17A. We hypothesize that similar associations between asthma severity and production of, or responsiveness to, Th17 cytokines is observed in asthmatic children.

METHODS: Nasal epithelial cells were collected from well-characterized pediatric asthmatics cohort. The cells were cultured and exposed to IL-13 and IL-17A to determine cellular responsiveness of a relevant primary cell type. Western blot analysis of STAT6 phosphorylation was used to measure IL-13 responses and ELISA analysis of CXCL1 production was used to measure IL-17A responses.

RESULTS: IL-13-induced phospho-STAT6 and IL-17A-induced CXCL1 production in nasal epithelial cells increases with asthma severity. The link between asthma severity and IL-13 responsiveness is more pronounced in males. IL-17A weakly augments IL-13-mediated phospho-STAT6 in mild and severe asthmatics and more strongly in moderate asthmatics. IL-13 suppresses IL-17A-mediated CXCL1 production.

CONCLUSIONS: Nasal epithelial cells responses to IL-13 and IL-17A vary proportionally with allergic asthma severity, suggesting that severity can be regulated at the level of cytokine responsiveness. Moreover, IL-17A augments IL-13-mediated responses while IL-13 suppresses IL-17A-mediated responses, providing a potential mechanistic explanation for increased susceptibility to bacterial and viral infections in allergic individuals.