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Wise et al.

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IL-13, 374 and ILC3s produce IL-17 and IL-22. 361 Type 2 ILCs are found in AR, where they closely interact with epithelial and other cells controlling the mucosal environment. Through the production of cytokines and induction of chemokines, a type 2 immune response is favored, supporting further development of an allergic tissue inflammation. 375 Although it was believed that IgE-producing B-cells reside in lymphoid follicles of the Waldeyer ring 376 and antibodies were then transferred to the mucosa, newer evidence has identified B-cells and plasma cells capable of producing IgE in nasal tissue of AR patients. 377 The local production of allergen-specific antibodies is further supported by the detection of secondary lymphoid tissue and IgE formation to Staphylococcus aureus in CRSwNP. 378 Within the nasal epithelium of allergic individuals increased numbers of major basic protein positive and EG2+ (activated) eosinophils can be encountered during the pollen season. Similarly, mast cells are found within the epithelium and the submucosal layer; however, no increases are observed in cell counts of T-lymphocytes or their subsets, nor of neutrophils or macrophages during seasonal allergen exposure. 379 Basophil numbers in the lamina propria of the nasal mucosa increase within 1 hour of allergen provocation. 380 Degranulation of both mast cells 381 and basophils occurs during the early and late phases of a type I reaction after allergen encounter and crosslinking of IgE molecules as well as upon stimulation by IL-33. 382 In the late phase of the allergic reaction, the influx of inflammatory cells is facilitated by chemoattractants and upregulation of adhesion molecules. 383 This leads to further infiltration of the tissue by eosinophils, basophils, and T-cells. Last, those inflammatory cells driving remodeling of the mucosa in AR, and upregulating factors such as matrix metalloproteinases and angiogenic factors, remain to be identified. 384 Cytokines are immunomodulatory proteins important in cellular signaling. Complex interactions of innate and adaptive immune cells, as well as structural cells and their cytokines, play crucial roles in regulating allergic airway inflammation. The inflammatory process underlying AR is coordinated by a network of cytokines. Type 2 cytokines such as IL-4, IL-5, IL-6, and IL-13 are crucial in regulating the allergic inflammatory cascade characterized by an increased presence of eosinophils and mast cells and an upregulation of IgE production. Besides their role in the induction of IgE synthesis, type 2 cytokines up-regulate the production of other cytokines and chemokines from epithelial cells and fibroblasts, 283 which then leads to the influx of inflammatory cells including eosinophils and mast cells. 385,386 Scadding et al. 387 demonstrated the immunological aspects of rhinitis with nasal allergen challenge. After nasal challenge with grass pollen in sensitive individuals, the levels of IL-4, IL-5, and IL-13 were elevated 2 to 3 hours postchallenge and increased for up to 5 or 6 hours. 387 Similarly, levels of chemokines such as thymus-regulated and activation-regulated chemokine (TARC, CCL17), macrophage derived chemokine (MDC, CCL22), eotaxin, RANTES, MCP-1, and macrophage inflammatory protein (MIP)-1 α were elevated. 388-391 Increases in these type 2 cytokines and associated chemokines were strongly correlated to allergic clinical responses.

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IV.E. Cytokine network and soluble mediators

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