Current concepts of severe asthma
Anuradha Ray, … , Prabir Ray, Sally E. Wenzel
Anuradha Ray, … , Prabir Ray, Sally E. Wenzel
Published July 1, 2016
Citation Information: J Clin Invest. 2016;126(7):2394-2403. https://doi.org/10.1172/JCI84144.
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Review

Current concepts of severe asthma

Abstract

The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care. Ongoing studies using advanced molecular and immunological tools along with improved clinical classification show that severe asthma does not identify a specific patient phenotype, but rather includes patients with constant medical needs, whose pathobiologic and clinical characteristics vary widely. Accordingly, in recent clinical trials, therapies guided by specific patient characteristics have had better outcomes than previous therapies directed to any subject with a diagnosis of severe asthma. However, there are still significant gaps in our understanding of the full scope of this disease that hinder the development of effective treatments for all severe asthmatics. In this Review, we discuss our current state of knowledge regarding severe asthma, highlighting different molecular and immunological pathways that can be targeted for future therapeutic development.

Authors

Anuradha Ray, Mahesh Raundhal, Timothy B. Oriss, Prabir Ray, Sally E. Wenzel

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Figure 2

Environmental influence on severe asthma and a complex relationship among the immune system, airway epithelial cells, and airway smooth muscle cells in the airways of severe asthmatics.

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Environmental influence on severe asthma and a complex relationship amon...
Allergens and/or other environmental agents with or without protease activity and different pathogens may elicit severe disease early or late in life. Therapies directed against various arms of the type 2 immune response based on the patient’s inflammatory response and other characteristics have shown promise in recent clinical trials. While an IFN-γ (Th1/type 1) immune response has been identified in different patient cohorts, no therapy has yet been directed against this arm of the immune response. IFN-γ can inhibit SLPI expression from airway epithelial cells. SLPI is a protease inhibitor secreted by airway epithelial cells that inhibits proteases present in different cell types (mast cells, neutrophils) and infectious agents. Protease-activated PAR2 on airway smooth muscle cells has been implicated in AHR in animal studies. IFN-γ and low levels of the type 2 cytokine IL-13 can synergize to induce nitro-oxidative stress in airway epithelial cells. Future studies will determine the potential role of ILC2s and of ILC2-activating cytokines such as IL-33 in severe asthma. Nasal polyps are also encountered in severe asthma, usually in late-onset disease, and crosstalk between the nasal mucosa and the airways may occur due to leakage of cytokines such as IL-5 from the local site (nose) of inflammation. APC, antigen-presenting cell.