This dissertation by Akshaya Saikumar Jayalatha describes research on the genetic, molecular, and functional implications for asthma of the biological activity of the cytokine IL-33 and the associated IL-1RL1 receptor on epithelial and immune cells. Asthma is a heterogeneous and complex respiratory disease, characterized by airway inflammation and hyperreactivity. Over 300 million people worldwide suffer from asthma. Treatment is primarily focused on symptom relief through the administration of corticosteroids and short- or long-acting beta-agonists, with progressively higher doses until symptoms are well controlled. However, the disease cannot be cured. A more personalized approach to asthma treatment, where specific biological mechanisms contributing to a patient's symptoms are targeted, may offer new opportunities for tailored therapies.
One of the biological mechanisms contributing to asthma is the cytokine IL-33, which is part of the IL-1 cytokine family. This cytokine acts as an alarm signal to trigger immune responses following cellular damage to barrier tissues. The IL-1RL1 protein is part of the heterodimeric IL-33 receptor and is involved in activating various immune and structural cells through IL-33, contributing to the development of a type 2 inflammation commonly seen in asthma.
The dissertation describes how genetic variation in the IL-33 and IL-1RL1 genes is associated with the strength of IL-33-driven gene expression (transcriptional effects) in different cell types, such as mast cells, Th2 cells, and epithelial cells. It also explores the implications of IL-33/IL-1RL1 signaling in the immunology of asthma, emphasizing the pathway’s contribution to the type 2 immune response associated with allergic inflammation.
