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Wise et al.

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Although type 2 cytokines were originally referred to as Th 2 cytokines after their suspected cellular source, several other cells have been identified as significant sources including mast cells, epithelial cells, type 2 ILCs, and eosinophils. Airway mast cells are an important source of type 2 cytokines, proinflammatory cytokines, chemokines, and the IL-7–like cytokine TSLP. 283,392-394 IL-13 from mast cells plays a crucial role in mast cell–induced local IgE synthesis by B cells, 286,395 which in turn upregulate Fc ε RI expression on mast cells. 286 Further, several mast cell products heavily influence epithelial cells. TNF- α , a proinflammatory cytokine produced by mast cells, in concert with IL-4 and IL-13, enhances the production of TARC, TSLP, and eotaxin from epithelial cells. 385 And chemokines such as tryptase and chymase can upregulate RANTES and GM-CSF production from epithelial cells. 385 Thus, there appears to be a crucial interplay between mast cells and epithelial cells in promoting and regulating the allergic inflammatory cascade. In addition to the cytokines and chemokines listed in the previous paragraphs, nasal epithelial cells are an important source for IL-1, IL-6, IL-8, and TNF- α . Through these signals, epithelial cells play a crucial role in the migration and activation of eosinophils, basophils, and Th2 cells. 396 In addition, epithelial cells release the cytokines IL-25, IL-33, and TSLP that orchestrate both the innate and adaptive Type 2 immune response. These same cytokines are also released by tissue damage, pathogen recognition, and allergen exposure. They can regulate Th2 cell function either directly or via innate lymphoid cells, which in turn produce IL-5, IL-9, IL-13, TSLP, IL-25, and IL-33, which are all increased in the nasal mucosa of AR patients, indicating a role of these cytokines in the pathophysiology of AR. 397-400 In fact, levels of IL-33 in nasal secretions have been shown to correlate with total nasal symptom scores. 400 Further, TSLP has been shown to activate dendritic cells, promote Th2 responses, and activate mast cells. 401 Eosinophils are another cell type that appears to play a significant role in the pathophysiology of AR. They are a major source of the inflammatory cytokines macrophage migration inhibitory factor (MIF) 402 and nerve growth factor (NGF). 403 Eosinophils express 5-lipoxygenase, LTC4S, and CysLT 1 and CysLT 2 receptors, which play a role in the arachidonic acid pathway. 404 IL-5 has a key role modulating eosinophil maturation, differentiation, and survival. 405 Eosinophilic chemoattractants include eotaxin, MCP4, RANTES, and cysteinyl leukotrienes, among others. 406-408 As discussed in earlier paragraphs within this section, mast cells and epithelial cells either directly produce or upregulate many of these same chemoattractants. Finally, Th17 cells are a unique subpopulation of CD4+ T cells. They produce IL-17A, IL-17F, IL-22, TNF- α , and IL-21. 409 They have been demonstrated to be in the nasal mucosa of AR patients and are therefore thought to play a role in allergic inflammation. 409,410 Further, IL-17A has been shown to be upregulated in SAR patients 5 hours after nasal allergen challenge. 411 Finally, increased numbers of IL-17A + cells and IL-17A mRNA were demonstrated in the nasal mucosa of patients with dust mite allergy, indicating a possible role in AR. 412

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In summary, AR is a type 2–mediated disease, characterized by important regulatory cytokines such as IL-4, IL-5, and IL-13. Newer type 2 cytokines have been identified in AR,

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