Allergic Bronchopulmonary Aspergillosis

Abstract

Allergic bronchopulmonary aspergillosis (ABPA), a progressive fungal allergic lung disease, is a common complication of asthma or cystic fibrosis. Although ABPA has been recognized since the 1950s, recent research has underscored the importance of Th2 immune deviation and granulocyte activation in its pathogenesis. There is also strong evidence of widespread under-diagnosis due to the complexity and lack of standardization of diagnostic criteria. Treatment has long focused on downregulation of the inflammatory response with prolonged courses of oral glucocorticosteroids, but more recently concerns with steroid toxicity and availability of new treatment modalities has led to trials of oral azoles, inhaled amphotericin, pulse intravenous steroids, and subcutaneously-injected anti-IgE monoclonal antibody omalizumab, all of which show evidence of efficacy and reduced toxicity.

Keywords: Aspergillus fumigatus; asthma; cystic fibrosis.

Figure 1

A hypothetical working model to describe the roles of molecular and cellular elements of the local innate response to Aspergillus in driving T helper type 2 adaptive immunity in the airway exposed to fungal allergens. In the resting condition, IL-33 is stored in the nucleus of airway epithelial cells. Exposure to fungal allergens (prominently including fungal proteases) induce the extracellular release of IL-33 and production of IL-25 and TSLP by the airway epithelium. Autocrine secretion of ATP and uric acid likely play a role in regulating epithelial release of IL-33. IL-33, IL-25, and TSLP activate innate lymphoid type 2 cells (ILC2) to produce a large quantity of type 2 cytokines including IL-5, IL-13, IL-9, and amphiregulin. Type 2 cytokines drive differentiation of B cells to secrete IgE (thereby sensitizing mast cells and basophils as allergic effectors) and attracting and activating eosinophils. IL-33, IL-25, and TSLP also act upon dendritic and naïve T cells to drive CD4+ T cell differentiation to a Th2 response. Basophil-derived IL-4 may facilitate ILC2 production of cytokines. ILC2-derived IL-13 enhances antigen uptake and migration of dendritic cells and promotes proliferation and differentiation of Th2-type CD4⁺ T cells. In addition, ILC2s and Th2-type CD4⁺ T cells may interact directly to sustain production of type 2 cytokines. Abbreviations: Baso, basophils; DC, dendritic cells; TSLP, thymic stromal lymphopoietin; ATP, adenosine triphosphate; IL, interleukin. Modified with permission from [22].