Complement Component 3C3 and C3a Receptor Are Required in Chitin-Dependent Allergic Sensitization to Aspergillus fumigatus but Dispensable in Chitin-Induced Innate Allergic Inflammation

Abstract

Levels of the anaphylatoxin C3a are increased in patients with asthma compared with those in nonasthmatics and increase further still during asthma exacerbations. However, the role of C3a during sensitization to allergen is poorly understood. Sensitization to fungal allergens, such as Aspergillus fumigatus, is a strong risk factor for the development of asthma. Exposure to chitin, a structural polysaccharide of the fungal cell wall, induces innate allergic inflammation and may promote sensitization to fungal allergens. Here, we found that coincubation of chitin with serum or intratracheal administration of chitin in mice resulted in the generation of C3a. We established a model of chitin-dependent sensitization to soluble Aspergillus antigens to test the contribution of complement to these events. C3−/− and C3aR−/− mice were protected from chitin-dependent sensitization to Aspergillus and had reduced lung eosinophilia and type 2 cytokines and serum IgE. In contrast, complement-deficient mice were not protected against chitin-induced innate allergic inflammation. In sensitized mice, plasmacytoid dendritic cells from complement-deficient animals acquired a tolerogenic profile associated with enhanced regulatory T cell responses and suppressed Th2 and Th17 responses specific for Aspergillus. Thus, chitin induces the generation of C3a in the lung, and chitin-dependent allergic sensitization to Aspergillus requires C3aR signaling, which suppresses regulatory dendritic cells and T cells and induces allergy-promoting T cells.

Innate Defense against Fungal Pathogens

“…ABPA pathogenesis is poorly understood, although recent insights have identified some mechanisms that may help future development of therapies. For example, dectin-1 recognition of A. fumigatus was recently shown to enhance immunopathology through IL-22 (Lilly et al 2012), whereas C3aR −/− mice presented with reduced allergic symptoms when sensitized with A. fumigatus chitin (Roy et al 2013). Other fungi that have been shown to exacerbate asthma are C. neoformans and Alternaria alternata, which induce trademark symptoms of allergy including eosinophilia and Th2 polarization (Goldman et al 2006; Doherty et al 2012).…”

Immune responses to ectoparasites of horses, with a focus on insect bite hypersensitivity

“…Conversely, false positive results may represent innate inflammatory responses to factors present in Culicoides extracts (56,57,80) such as proteases that could directly trigger mast cell degranulation by activating PAR receptors (32). Alternatively, false positive reactions could be caused by cross-reactive carbohydrate antigens which are known to cause false positive results in human intradermal testing (81) or possibly the presence of Chitin derived from arthropod exoskeleton within the allergen extracts, which in large molecular weight form can have pro-allergenic inflammatory effects (82,83).…”

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

“…Aspergillus fumigatus infections have not been explicitly modeled in AP-modified animals. However, in murine models of fungal allergy, this pathway has been involved in the chitin-dependent production of C3a in the lung, a process that suppresses regulatory dendritic and T cells, and supports allergy-promoting T cells, via C3a receptor (C3aR) [78]. Similarly, repeated intranasal inoculation of immunocompetent mice with A. fumigatus conidia exposing high levels of chitin skewed T-helper cells toward a type-2 allergic response [79].…”