PULMONARY INNATE LYMPHOCYTES AND AIRWAY INFLAMMATORY RESPONSES TO ALLERGENS AND AIRBORNE PARTICULATES

Maria Martin Ferrini

Abstract

The incidence of asthma continues to rise and is estimated affect nearly 340 million people globally. In the U.S., asthma affects approximately 10% of both adult and child populations. While asthma does have different phenotypes the most common form of the disease, affecting 80% of children and the majority of adult asthmatics, is allergic asthma. This phenotype consists of dysregulated type-2 immune responses to aeroallergens. Underlying risk factors for asthma are poorly understood, however factors linked to asthma incidence include genetic predisposition, early life exposure to certain respiratory viruses and a wide range of environmental exposures such as to products of biomass combustion, as evidenced by increased asthma incidence following smoke exposure whether in-home or outdoors. As the knowledge concerning asthma continues to accumulate, there is an increased understanding that asthmatic responses rely on a coordination of both innate and adaptive immune responses. In response to allergens such as house dust mite proteins (HDM) the airway epithelial cells release a range of alarmins, most notably, IL-25, IL-33 and TSLP who’s primary function is to activate type-2 innate lymphoid cells (ILC2) and promote the release of IL-5 and IL-13. In order to study ILC2 mediated responses in the lung we developed three models of pulmonary exposures to facilitate the dissection of the cellular and molecular properties of ILC2s during lung inflammatory processes. The first entailed the instillation of IL-33 into the airways of mice, the second approach involved the instillation of HDM allergen and the third approach involved prenatal exposures to wood smoke or filtered air followed by PBS or HDM instillation. These three exposures were all associated with increased levels of IL-33 and active TGF- b1 in the lung (BALF) and increased numbers of CD103+ ILC2s within the lung. These studies together point to a previously unidentified role for TGF-b in the induction of CD103 expression on ILC2s during pulmonary inflammatory responses. These CD103+ ILC2s appear to play a very important role in not only the instigation of inflammatory responses but in their persistence via their proximal monitoring of the lung epithelial surfaces and cytokine production in response to subsequent exposures.