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Thursday, July 2, 2015

Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33

Little is known about the mechanisms regulating the persistence of chronic asthma. Because many allergens are perennially present, it has been difficult to ascertain whether persistence depends on this proximity. Studies of patients with occupational asthma have shown they experience symptoms for years after occupational exposure has ended. Christianson et al developed a mouse model in which asthma persisted for six months after allergen exposure ceased. They then used a combination of immunologic, genetic, microarray, and pharmacologic approaches to identify the factors contributing to symptom persistence (J Allergy Clin Immunol 2015; 136(1):59-68).

The authors found increased ILC2 levels characterize chronic asthma. In addition, IL-33-driven ILC2s prove to be an essential factor. The blockade of epithelial IL-33 led to a complete resolution of airway hyperactivity and a significant reduction of airway inflammation. They found IL-13, a product of ILC2s, can induce production of IL-33. It also generates a forward-feed mechanism on IL-33R expression, creating a positive feedback loop. Elimination of any component of the circuit resulted in disease resolution. They found finally that elimination of T-cells resolved airway inflammation but not airway hyperactivity or remodeling.

While previous studies have shown increased IL-33 in bronchoalveolar lavage (BAL) fluid, here the authors demonstrate an increase in ILC2 numbers. The results have implications for the treatment of chronic illnesses in general, suggesting that they depend on feedback and feed-forward circuits, interconnected systems that fail if a component is removed, and that it is these circuits that transition a disease from an acute condition to a chronic one.

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