Innate immune responses in house dust mite allergy

Abstract

Sensitizations to house dust mites (HDM) trigger strong exacerbated allergen-induced inflammation of the skin and airways mucosa from atopic subjects resulting in atopic dermatitis as well as allergic rhinitis and asthma. Initially, the Th2-biased HDM allergic response was considered to be mediated only by allergen B- and T-cell epitopes to promote allergen-specific IgE production as well as IL-4, IL-5, and IL-13 to recruit inflammatory cells. But this general molecular model of HDM allergenicity must be revisited as a growing literature suggests that stimulations of innate immune activation pathways by HDM allergens offer new answers to the following question: what makes an HDM allergen an allergen? Indeed, HDM is a carrier not only for allergenic proteins but also microbial adjuvant compounds, both of which are able to stimulate innate signaling pathways leading to allergy. This paper will describe the multiple ways used by HDM allergens together with microbial compounds to control the initiation of the allergic response through engagement of innate immunity.

Figure 1

Allergenic determinants associated to house dust mite. The identified HDM allergens present in mite bodies and faeces display, together with IgE-binding and T-cell epitopes, at least one allergenic determinant able to trigger innate immunity: glycan structure to engage CLRs, hydrophobic pocket to transport lipids which, in turn, can stimulate TLRs, and protease activity to activate PAR-2 and more likely other cell surface receptors. HDM allergens are commonly associated with microbial endosymbiotic PAMPs from the house dust including at least LPS, β-glucans, chitin, and flagellin (crystal structure of cell-surface flagellin 2ZBI from RCSB PDB).

Figure 2

Simplified model of the HDM-induced innate immune activation leading to allergic asthma. The induction of Th2 immunity by HDM allergens results from the stimulations of different innate immune pathways. HDM protease allergens specifically cleave protease-sensitive receptors including PAR-2, disrupt epithelial barrier to gain access to DCs, and cause tissue injuries to release DAMPs such as ATP and uric acid. Contaminating microbial PAMPs associated or not with lipid-binding allergens trigger numerous PRRs which can produce also DAMPs whereas HDM glycan activation of DCs is mediated through CLR ligation. These signaling pathways result in the massive upregulation of innate cytokines/chemokines as IL-1β, IL-6, TSLP, IL-25, IL-33, GM-CSF, or CCL20 to recruit and activate inflammatory cells and to induce Th2 differentiation. Notably, TSLP mediates OX40L and IL-4 expression in DCs and basophils, respectively, to initiate Th2-polarized response. IL-25 as well as IL-33 are strong activators of ILC2s which, similar to allergen-specific Th2 cells, provide large amount of the Th2 cytokines IL-5 and IL-13 to generate the main features of the allergic airway inflammation such as IgE secretion by B cells, eosinophil recruitment, and airway remodeling.