Rethinking Severe Asthma: The Airway Epithelium as an Immune Organ

Welcome back to another HCPLive Peer Exchange series. In "Rethinking Severe Asthma: The Airway Epithelium as an Immune Organ," moderator Geoffrey Chupp, MD is joined by Jacqueline Ross, MD, Michael E. Wechsler, MD, MMSc, and Nicola A. Hanania, MD, MS to open the series on severe asthma and upper airway disease.

Dr. Chupp frames the opening question for Dr. Ross, whose allergy career centered on the immunologic side of airway disease. Dr. Ross says clinicians once pictured the epithelium as a brick wall built only to keep things out. That picture no longer holds. She describes the epithelium as an immune system and an organ in its own right. It produces chemicals and cytokines that recruit cells to the site to fight pathogens. It holds mediators such as IgA at the surface that neutralize threats on contact. Innate immune cells sit there ready to activate against viral, bacterial, and other pathogens. The tissue can also drive an adaptive response and build a kind of protective memory. When that system is disrupted, she explains, inflammation and irritation follow, producing airway remodeling, excess mucus, and further destruction of the epithelium itself.

Dr. Wechsler agrees and extends the point to mechanism. He describes an immune-modulating tissue that releases cytokines capable of shaping the entire immune response. The epithelial cytokines, or alarmins, include IL-25, IL-33, and thymic stromal lymphopoietin. These activate TH2 cells and innate lymphoid cells, which in turn release the cytokines that drive asthma. He walks through each one. IL-4 fuels the allergic pathway and downstream IgE production. IL-5 drives the activation, proliferation, and maturation of eosinophils. IL-13 plays what he calls a variegated set of roles, contributing to mucus production, airway hyperresponsiveness, fibrosis, and nitric oxide. His conclusion sets up the series: acting at the epithelial layer produces consequences across many cells and many cytokines at once.

The next episode in this series, "Alarmins and TSLP and Upstream Drivers of Severe Asthma Inflammation," features Dr. Hanania on why one epithelial cytokine sits above all the others.