Blood biomarker panels of the late phase asthmatic response

Individuals with allergic asthma respond differently, but reproducibly, to allergen inhalation challenge. Some individuals develop an early response only (isolated early responders, ERs) while others also go on to develop a late response (dual responders, DRs). The early asthmatic response is characterized by acute airway contraction immediately following allergen inhalation and resolves within 1-3 hours. 60% of asthmatic individuals go on to develop a late asthmatic response that occurs 3-4 hours after allergen inhalation and is characterized by prolonged airway contraction, cellular infiltration of the airways, chronic inflammation, and airway remodeling. It is not understood why late responses do not develop in all sensitized individuals. In this thesis, I combined the power of the allergen inhalation challenge model to study airway responses with unbiased high throughput technologies and data driven computational methods to delineate molecular differences between ERs and DRs using peripheral blood. I identified many markers that discriminated ERs and DRs such as fibronectin, many pro-inflammatory, anti-inflammatory and cell-specific genes, lipid metabolites and amino acids and the T helper type 17 to T regulatory cell (Th17/Treg) ratio. Transcriptional biomarker panels performed well (AUC ~70%) in predicting at risk/susceptible individuals for the late phase asthmatic response prior to allergen challenge. These panels depicted a heightened pro-inflammatory (activation of nuclear factor (NF)-B signaling) and dampened anti-inflammatory (reduced expression of decoy and formyl peptide receptors which are involved in host response to pathogens) phenotype in DRs compared to ERs. I developed a statistical method which I used to identify multi-omic biomarker panels (cells, gene transcripts and metabolites). The identified panels achieved a systems view of the underlying molecular interactions highlighting common pathways such as lipid metabolism and valine, leucine and isoleucine metabolism across different biological compartments. I demonstrated that inherent molecular differences in blood exist between ERs and DRs suggesting that some asthmatic individuals display early systemic indications of chronic asthma. These findings may be used to develop blood tests to risk-stratify subjects to improve response to therapies, and may lead to earlier and accurate diagnoses.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat