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Wise et al.

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recent study showed that 83% of LAR subjects sensitized to Olea europaea pollen responded to NPT with nOle e 1 (the most significant allergen of Olea europea ), demonstrating that purified allergens can also induce an allergic response with secretion of ECP. 308 Local sIgE production.: The respiratory airway mucosa is a site of IgE production during allergic inflammation, as has been demonstrated in patients with AR 309-312 and LAR, 299-301,303-307 with both somatic hypermutation and class switching occurring in the nasal mucosa. 309,312-315 Cellular studies have confirmed the expression of ε -germline gene transcripts and messenger RNA (mRNA) for the ε heavy-chain of IgE in nasal mucosal B cells. 310 The rate of local IgE production 316 is sufficient to saturate IgE receptors on local mast cells, and potentially spill over into the circulation. 316,317 In LAR, the presence of sIgE in nasal secretions has been confirmed after natural allergen exposure, 300,301 NPT, 300,301,303-305 and periods of non-exposure. 300,301 Furthermore, local sIgE in LAR has the capability of activating basophils via the high-affinity receptor Fc ε RI, leading to the release of inflammatory mediators characteristic of AR. 308,318 It is commonly accepted that AR is primarily an IgE-driven response. 319 However, in recent years our understanding and appreciation of the important contributions of the nasal innate immune response to the pathogenesis of AR has grown substantially. 320 The pathophysiologic mechanisms of inflammatory airway disease are related to large physiologic networks that influence host-environment interactions. The nasal epithelium is the first structure to encounter inhaled aeroallergens. Intrinsic proteolytic activity of allergens may disrupt the nasal epithelial barrier, facilitating allergen penetration and chronic inflammation. 321 Recent data provide additional evidence that epithelial barrier dysfunction contributes to the development of inflammatory diseases such as AR, but it remains to be elucidated to what extent primary (genetic) vs secondary (inflammatory) mechanisms drive this breakdown. 322 Epithelial cells not only act as a physical barrier toward inhaled allergens, but also actively contribute to airway inflammation by detecting and responding to environmental factors. The nasal epithelium expresses pattern recognition receptors in the form of toll-like receptors (TLRs) that, after activation by allergens or pathogens, lead to the production of different mediators. 323,324 These mediators affect recruitment of inflammatory cells to local tissues and create a microenvironment that affects the function of immune cells, thereby propagating local inflammatory processes. 325 In allergic disease, the nasal epithelium seems to be in a permanently activated state, 326 potentially as a consequence of the inability to switch off the activation response. 327 An interesting recent development was the discovery of innate lymphoid cells (ILCs) as potential key players in the pathogenesis of Th2-type diseases such as AR, CRSwNP, and asthma. 328-330 ILCs are a family of effector cells that are important for protection against infiltrating pathogens and restoration of tissue integrity. ILCs do not express antigen-specific T-cell receptors, but can react promptly to “danger signals” and produce an array of cytokines that direct ensuing immune responses. Three major subsets have been defined based on their phenotype and functional similarities to Th1 (ILC1), Th2 (ILC2), and Th17 (ILC3) cells. Upon exposure to environmental antigens, including viruses and allergens,

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IV.B. Non–IgE-mediated inflammation in allergic rhinitis

Int Forum Allergy Rhinol . Author manuscript; available in PMC 2020 June 10.