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Wise et al.

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airway epithelial cells rapidly release the cytokines IL-25, IL-33, and TSLP which directly activate ILC2s that then produce the prototypical type 2 cytokines IL-5 and IL-13. 331 Allergen challenge in AR subjects induces an increased number of peripheral serum ILC2s 332,333 ; however, a similar increase in the nasal mucosa is yet to be demonstrated. In addition to treatments aimed at modulating IgE-mediated inflammation, novel therapies directed toward the innate immune system are in development for treatment of AR. 334,335 The upper and lower airways are linked from anatomical, histological, and immunological perspectives with inflammation in one part of the airways influencing the other part, thus forming a united airway system. 336 New systemic treatment options make understanding of the relationship between upper and lower airways even more important. 337 The mucosa of the upper and lower airways is similar, containing pseudostratified epithelium with ciliated columnar cells lining. Basal epithelial cells are also present, attached to the basement membrane ( lamina reticularis ), and have an epithelial stem cell function. In the submucosa there are vessels, mucus glands, fibroblasts, and some inflammatory cells. The main difference in mucosal components is the absence of smooth muscles in the upper airways as compared to the lower airways, and the lack of extensive subepithelial capillaries, arterial systems, and venous cavernous sinusoids in the lower airways as compared to the upper airways. The characterization of phenotypes of rhinitis and asthma are very similar, with emphasis on allergy and eosinophilia, non-allergic phenotypes in both upper and lower airways, and the link between CRS, especially with nasal polyps, and late onset asthma. 319,338,339 Both AR and asthma may also be characterized by hyperreactivity that is not correlated to the atopic state. 192,340 Also in endotyping, similarities can be pointed out with emphasis on type 2 vs non-type 2 immune responses. In allergic diseases, the prominent endotype is type 2 (eg, Th2 cells, type 2 B-cells, IL-4-producing natural killer [NK]/T cells, basophils, eosinophils, mast cells, ILC2, IL-4, IL-5, IL-13, IL-25, IL-31, IL-33). 319,341 In general, the type 2 profile in AR and asthma is associated with a good response to corticosteroid treatment. New targeted treatments that focus on (subgroup) type 2 elements, such as anti-IgE antibodies, anti-IL-5 (mepolizumab), and anti-IL-4/IL-13 (dupilumab) are currently used in asthma, but are not currently approved for use in the upper airways. 342 Similarities are not only found in the acquired immune response, but also in the role of innate immunity like epithelial barrier function 334 and innate lymphoid cells. 332 Epithelial barrier leakiness, particularly tight junctions that seal the upper and lower respiratory mucosal epithelial surface, has been shown in asthma, AR and CRS. 343,344 Several mechanisms may explain the influence of sinonasal inflammation on the lower airways; ie, altered breathing pattern, pulmonary aspiration of nasal contents, the nasobronchial reflex, and the uptake of inflammatory mediators in the systemic circulation. 345 The nose acts as a filter and air conditioner, protecting the lower airways. Reduced filter and air-conditioning functions of the nose may lead to increased exposure of the lower airways to allergens. Mouth breathing is independently associated with asthma morbidity, indicating that air conditioning can be of major importance. The efficacy of the nasal filter

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IV.C. Unified airway concept

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