Airway Mycosis and the Regulation of Type 2 Immunity

Abstract

Filamentous fungi of the Aspergillus genus and others have long been linked to the induction of type 2 immunity that underlies IgE-mediated hypersensitivity responses. This unique immune response is characterized by the production of the allergy-associated T helper cell type 2 (Th2) and Th17 cytokines interleukin 4 (IL-4), IL-13, and IL-17 that drive IgE, eosinophilia, airway hyperresponsiveness and other manifestations of asthma. Proteinases secreted by filamentous fungi promote type 2 immunity, but the mechanism by which this occurs has long remained obscure. Through detailed biochemical analysis of household dust, microbiological dissection of human airway secretions, and extensive modeling in mice, our laboratory has assembled a detailed mechanistic description of how type 2 immunity evolves after exposure to fungi. In this review we summarize three key discoveries: (1) fungal proteinases drive the type 2 immune response; (2) the relationship between fungi, proteinases, and type 2 immunity is explained by airway mycosis, a form of non-invasive fungal infection of the airway lumen; and (3) the innate component of proteinase-driven type 2 immunity is mediated by cleavage of the clotting protein fibrinogen. Despite these advances, additional work is required to understand how Th2 and Th17 responses evolve and the role that non-filamentous fungi potentially play in allergic diseases.

A scoping review: What are the cellular mechanisms that drive the allergic inflammatory response to fungal allergens in the lung epithelium?

“…By collating and comparing the data extracted from the 61 studies, potential mechanisms within airway epithelial cells that drive fungal‐induced allergic responses (Figure 3) have been identified. However, it should be noted that many of the studies within this review used fungal CFE as an exposure compound in contrast to spores, which may not be a physiologically relevant method of exposure for humans on a day‐to‐day basis 16 …”

“…11 These disorders include asthma, chronic rhinosinusitis (CRS) and allergic bronchial pulmonary aspergillosis (ABPA), which affect millions of people globally. 1,[14][15][16][17] Typically, AAD is defined as an allergic response in individuals characterised by increased serum IgE, airway inflammation, airway remodelling (including peribronchial fibrosis and increased collagen deposition), increased type 2 cytokine profile (e.g. Interleukin (IL) 4, IL5, IL13, IL25, IL33, thymic stromal lymphopoietin (TSLP)), airway eosinophilia, mucus hypersecretion, and airway hyperresponsiveness (AHR).…”

“…However, it should be noted that many of the studies within this review used fungal CFE as an exposure compound in contrast to spores, which may not be a physiologically relevant method of exposure for humans on a day-to-day basis. 16 Epithelial barrier disruption is a key mechanism in AAD and has been identified as a target mechanism. As many reviews have been published on the disrupted epithelial barrier in allergy and asthma, 18,20,97 we have not included a section on the epithelial barrier in this review and included information related to fungi in the sections below.…”

“…Allergic airway disease (AAD) is a collective term for respiratory disorders that can be exacerbated upon exposure to airborne allergens, including fungal agents, pollen and house dust mite (HDM) 11 . These disorders include asthma, chronic rhinosinusitis (CRS) and allergic bronchial pulmonary aspergillosis (ABPA), which affect millions of people globally 1,14–17 …”

“… 11 These disorders include asthma, chronic rhinosinusitis (CRS) and allergic bronchial pulmonary aspergillosis (ABPA), which affect millions of people globally. 1 , 14 , 15 , 16 , 17 …”