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Wise et al.
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response can be broadly classified into 2 categories based upon the predominant Th lymphocyte subtype. 274 The Th1 profile is responsible for defense against intra-cellular pathogens, while Th2 responses are implicated in the defense against parasitic infections as well as the IgE-mediated eosinophilic inflammation of allergy. 272 Whether AR will develop as a result of inhalant allergen exposure therefore depends largely upon the balance between Th1 and Th2 effector cells. 274 A number of steps in the sensitization process are responsible for eliciting the Th2 predominant response. The process begins with exposure of the nasal mucosa to inhalant allergens. 275 While mucosal epithelial cells were once thought to function simply as a mechanical barrier to allergen penetration, recent research suggests that epithelial cells play a much more sophisticated role in allergy development, through the secretion of numerous inflammatory mediators including cytokines, chemokines, eicosanoids, and endopeptidases, as well as through upregulation of cellular adhesion molecules and release of matrix metalloproteinases. 276 They also provide an important early stimulus toward a Th2-weighted immune response, through the secretion of thymic stromal lymphopoietin (TSLP). 272,275,276 TSLP causes maturation of dendritic cells into Th2-promoting subtypes, 277 which secrete chemokines that attract Th2-destined T lymphocytes, foster clonal amplification of Th2 cells, and enhance survival of memory B-cells. 272 TSLP also promotes recruitment of eosinophils and enhanced activity of basophils and mast cells. 272 Allergens are then engulfed by dendritic cells, which migrate to lymphoid organs where the antigen is presented to naive helper T (Th0) cells on MHC class II molecules. 274 Th2 differentiation also requires co-stimulation via the interaction of CD28 on T cells with CD80 and CD86 on antigen-presenting cells (APCs). 278 Additionally, the presence of the cytokine IL-4 is required. 279 IL-4 binds STAT-6 on the Th0 cell, activating the master switch GATA-3. 272 This stimulates IL-4, IL-5, and IL-13 production, 274 which is characteristic of the Th2 response. These cytokines, produced by the newly differentiated Th2 cell, have several effects that further promote IgE-mediated eosinophilic inflammation and allergy. IgE is produced by B-cells under the influence of Th2 effector cells and the cytokines they secrete. 275 Development of an IgE-secreting B cell requires the presence of IL-4 or IL-13, which induce class switching via upregulation of ε -germline gene transcription and clonal expansion, as well as interaction between CD40 ligand on the T-cell surface and CD40 on the B-cell surface, which promotes B-cell activation and the production of IgE. 279 Allergen specific IgE (sIgE) is then released into the circulation by plasma cells. IgE antibodies subsequently bind high-affinity receptors (Fc ε RI) on the surface of mast cells and basophils, rendering them sensitized. 280 Future allergen exposure results in crosslinking of IgE on the surface of mast cells and basophils causing degranulation, release of inflammatory mediators such as histamine, and the classic symptoms of AR. IV.A.2. IgE-IgE receptor cascade— IgE plays a central and defining role in the pathophysiology of acute allergic reactions as well as chronic atopic disease. 281 In individuals with AR, exposure to specific allergens results in the production of allergen specific IgE, which then binds to effector cells such as mast cells and basophils via the high
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Int Forum Allergy Rhinol . Author manuscript; available in PMC 2020 June 10.
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