The role of interleukin-17 in airway inflammation in asthma. (360G-Wellcome-088365_Z_09_Z)

Asthma affects 150 300 million people worldwide, inflicting significant morbidity, mortality and financial cost. Disease heterogeneity is increasingly recognised, but the underlying mechanisms, especially in the severe neutrophilic asthma phenotype, remain unclear. Aberrant responses to viral infection play an acknowledged role in asthma exacerbations, but their immunological correlates are poorly understood. The recently described cytokine interleukin-17, whose expression characterises the nove l T helper-17 (TH17) lymphocyte subset, may play a critical role in both these areas. I hypothesise that a dysregulation of the balance between TH17 and regulatory T (TREG) cell subsets may underlie, and help define the severe neutrophilic asthma phenotype. I also hypothesise that in asthma an aberrance of the TH17: TREG response to respiratory pathogens, particularly viruses, contributes to the development of exacerbations. I propose to characterise TH17 cells in airway inflammation in three contexts: in a cross-sectional study of severe asthma, mild-to-moderate asthma and health; and in longitudinal studies during naturally occurring asthma exacerbations, and during in vivo challenge with human rhinovirus. The anticipated practical outputs of this work include a deepened understanding of the role of IL-17 in the pathogenesis of asthma, and potentially the identification of new biomarkers for asthmatic phenotypes and new therapeutic targets.