xRead - September 2022

Wise et al.

Page 33

including IL-17 family cytokines. Finally, Type 2 ILCs and epithelial cell-derived cytokines such as TSLP, IL-25, and IL-33 play a crucial role in the regulation of the allergic inflammatory cascade.

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

IV.F. Histologic and epithelial changes

Normal nasal mucosa comprises pseudostratified columnar ciliated epithelium with goblet cells over a basement membrane. The nasal submucosa contains stromal elements including fibroblasts, blood vessels, seromucinous glands, sensory nerves, and leukocytes. Leukocytes present in the nasal mucosa include CD4+ and CD8+ T lymphocytes, B lymphocytes, eosinophils, neutrophils, basophils, mast cells, and macrophages. The combined functions of ciliated and secretory cells allow for nasociliary clearance, removing pathogens and allergens as a host defense mechanism. In addition to the physical barrier, nasal epithelium plays an important role in the innate and acquired immunologic defense against pathogens 359,413,414 by: (1) expressing pattern recognition receptors that recognize pathogen-associated molecular patterns; (2) secreting a vast arsenal of host defense molecules, such as antimicrobial enzymes, opsonins, permeabilizing proteins, collectins, and binding proteins; and (3) producing inflammatory cytokines in response to antigenic stimuli. Allergy mediates epithelial change in the nasal mucosa. Nasal epithelium is thicker in patients with AR after allergen challenge, 415,416 but studies on epithelial thickness in AR without allergen challenge are conflicting. 415-417 While epithelial remodeling is a key feature of CRS (epithelial hyperplasia, goblet cell hyperplasia, and squamous metaplasia) 418-420 and asthma (epithelial desquamation, subepithelial fibrosis, and smooth muscle hypertrophy), remodeling in AR is less marked. In general, limited studies have found no significant increase in basement membrane thickness, subepithelial fibrosis, goblet cell hyperplasia, or blood vessel volume and surface density, 415,421,422 though increased vascular permeability was noted. 423 In contrast to epithelial remodeling, epithelial inflammatory response to allergens is a key feature of AR. Upon allergen exposure, there is significantly higher infiltration of inflammatory cells, and increased levels of cytokines (such as IL-4, IL-5, and IL-13) in the nasal epithelium of allergic compared to non-allergic patients. 182 This inflammatory response translates into mucosal edema, autonomic neural stimulation, and increased mucosal secretions, which manifest as the hallmark symptoms of nasal obstruction, pruritus, sneezing, rhinorrhea, and smell loss in severe cases. The epithelial barrier is noted to have specific functions in allergy. Penetration of allergens through this barrier may lead to allergen sensitization and local and/or systemic inflammatory response. In the nasal mucosa, this barrier is comprised of mucus and epithelial cells, which are linked by apical junctional complexes (tight junctions and adherens junctions). 367 Mechanical or infective insults to the epithelium or defective epithelium leads to barrier breach and allergen penetration. 367,424-426 Loss-of-function mutations and polymorphisms in genes coding for epithelial barrier markers such as filaggrin are associated with AR and eczema. 427,428 Some allergens can induce junctional dysfunction, leading to penetration of the epithelial barrier by allergens. 322,429 Proteolytic allergens directly disrupt the apical junctional complex via proteolysis, leading to barrier dysfunction. 430 Detection of allergens by APCs, and the ensuing Th2 responses and

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