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Wise et al.

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identified cells such as type 2 ILCs, Th17 cells, and Th22 cells, have been mostly restricted to investigations of peripheral blood cells, not tissue biopsies. There is evidence from a limited number of studies that different cells are involved at different stages of inflammation, such as exacerbation, remission, and extensive remodeling. Furthermore, different tissue sites such as sinus mucosa, polyp tissue, or inferior turbinates show a variety of different infiltrating immune and inflammatory cells. Nasal epithelial cells are at the interface of the human body and the environment, and often act as the first line of defense against external pathogens. Epithelial cells interfere with non self allergens and regulate infiltrating cells in AR through the production of various co stimulatory molecules, chemokines, cytokines, and lipid mediators. These cytokines start to orchestrate a type 2 immune response characteristic of AR. 356 However, when allergens have additional protease activity and/or they are accompanied by microbial components such as endotoxins or inorganic particles, epithelial secretory responses can lead to mixed type 2 and type 17 immunity, or even type 1 responses. 357,358 In response to respiratory viruses, epithelial cells produce a wide range of mediators such as type I interferons, granulocyte macrophage colony-stimulating factor (GM-CSF), RANTES/C-C Motif Chemokine 5 (CCL5), and interferon gamma-induced protein 10/C-X-C Motif Chemokine 10 (IP-10/ CXCL10). 359 These mediators orchestrate further downstream innate and adaptive antiviral cellular immune responses. To activate allergen-specific CD4 T-cells, adequate co-stimulation is required. Dendritic cells are professional APCs that are directly related to AR, with increased numbers and concentrations of IgE in atopic disease. 360 They are in close contact with epithelial cells and ILCs and control T-cell and B-cell activation and differentiation. 356 Also, elimination of dendritic cells has been shown to suppress the development of AR. 360 Both innate and effector mechanisms play essential roles during the development of allergic disease. 361 T-helper subset imbalance and production of typical Th2 cytokines, 362 along with increased expression of GATA-3, 363 is generally seen in AR nasal mucosa. Furthermore, CD4+ memory T-cells and gamma/delta-T-cells are increased in PAR patients’ mucosa. 364 Effector Th2 cells produce IL-4, IL-5, IL-9, and IL-13. 356,365 In addition, TSLP, IL-25, IL-31, and IL-33 contribute to the development and intensity of Th2 responses and inflammation. These cytokines have roles in production of sIgE, eosinophilia, mucus, tissue migration of Th2 cells and eosinophils, regulation of tight junctions, and epithelial barrier integrity. 343,356,366,367 T-regulatory (Treg) cell subsets have distinct phenotypes and include constitutive and inducible subsets of CD4+CD25+ Forkhead box P3 (FOXP3)+ Treg cells, and type 1 Treg cells. 368-370 Treg cells play a major role in allergen tolerance and allergen immunotherapy (AIT). 371-373 The production of IL-10 and transforming growth factor (TGF)- β from other cells is decisive for their immune regulatory functions. The ratio between effector and regulatory cell types determines whether an allergic response is triggered by an allergen or not. Populations of lymphoid cells that lack rearranged antigen receptors and markers for myeloid and lymphoid lineages, such as T-cells, B-cells, and NK-cells have been defined as ILCs. Type 1 ILCs (ILC1) mainly produce interferon (IFN)- γ , ILC2s produce IL-5 and

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