House dust mite (HDM) is an indoor aeroallergen which is commonly associated with the development of allergic rhinitis and allergic asthma. In fact, up to 70% of allergic asthmatic individuals have been shown to demonstrate reactivity towards HDM allergens. The downstream adaptive immune response to HDM is well characterize and is described as being largely T helper cell type 2 (Th2) and partly T helper cell type 17 (Th17) dominated. However, less is known about how resident antigen presenting cells (APCs) and structural cells such as airway epithelial cells recognize and respond to HDM. Unlike other microbial antigens, recognition of HDM is not primarily mediated through pattern recognition, rather by an intrinsic enzymatic or lipid-binding ability or by specific prost-translational modifications such as glycosylation. Various innate immune receptors, such as toll-like receptors (TLRs), C-type lectin receptors (CLRs), and protease-activated receptors (PARs), found on the surface of APCs and airway structural cells, have been demonstrated to be important in response to HDM. Nonetheless, the exact mechanisms by which these receptors or other undescribed receptors or molecules promote adaptive immunity, particularly Th2 immunity, is unclear. Using knock-out mice, we have shown that the kinase RIP2, which functions downstream of the peptidoglycan receptor NOD2, is involved in the early response to HDM likely within AECs and that its activation promotes airway inflammation. In follow-up work, we also demonstrate that early and acute pharmacologic inhibition of this kinase in a HDM asthma model has lasting effects on the reduction of airway inflammation and type 2 immunity associated with the pathology. The third project describes the identification of a novel receptor for HDM, LMAN1. We find that LMAN1 on dendritic cells functions to inhibit inflammatory responses to HDM and that loss of LMAN1 enhances airway inflammation in an asthma model. Altogether, my work has contributed to our understanding of the early events and molecules involved in responding to HDM. Our hope is that these findings will be useful in the discovery and testing of new therapies for treatment of allergic disease.
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Doctor of Philosophy (Ph.D.)
College of Medicine
Length of Campus-only Access
Doctoral Dissertation (Open Access)
Miller, Madelyn, "The Innate Immune Response to House Dust Mite in Allergic Airway Inflammation" (2020). Electronic Theses and Dissertations, 2020-. 383.