PATHOPHYSIOLOGY
Allergic rhinitis Allergic rhinitis is an atopic disease presenting with symptoms of sneezing, nasal congestion, clear rhinorrhea, and nasal pruri- tis (Wheatley & Togias, 2015). When persons are exposed to an allergen against which they are sensitized, cross-linking by the al- lergen of IgE bound to mucosal mast cells results in nasal symp- toms within minutes. This is due to the release of neuroactive and vasoactive substances such as histamine, prostaglandin D2, and cysteinyl leukotrienes. During the following hours, there is a complex interaction of mast cells, epithelial cells, dendritic cells, T cells, innate lymphoid cells, eosinophils, and basophils, and type 2 (Th2) inflammation develops in the nasal mucosa with the par - ticipation of a wide array of chemokines and cytokines produced by these cells. Because of mucosal inflammation, nasal symptoms
can persist for hours after allergen exposure (Wheatley & Togias, 2015). The mucosa becomes more reactive to the precipitating allergen (priming), other allergens, and nonallergenic stimuli such as strong odors and other irritants (nonspecific nasal hyperrespon - siveness). Non-IgE-mediated hyperresponsiveness can develop due to eo- sinophilic infiltration and nasal mucosal destruction. The nasal mucosa now becomes hyperreactive to normal stimuli (such as tobacco smoke and cold air), which produces symptoms of sneez- ing, rhinorrhea, and nasal pruritis. While there are data to suggest a genetic component to allergic rhinitis, high-quality studies are lacking (Skoner, 2001). Sensitization entails allergen uptake by antigen-presenting cells (dendritic cells) at a mucosal site, leading to activation of anti- gen-specific T cells, most likely at draining lymph nodes. Simul - taneous activation of epithelial cells by nonantigenic pathways (e.g., proteases) can lead to the release of epithelial cytokines (thymic stromal lymphopoietin [TSLP], interleukin-25, and inter- leukin-33), which can polarize the sensitization process into a type 2 helper T (Th2) cell response. This polarization is directed toward the dendritic cells and most likely involves the participation of type 2 innate lymphoid cells (ILC2) and basophils, which release Th2-driving cytokines (interleukin-13 and interleukin-4). This pro- cess results in the generation of Th2 cells, which, in turn, drive B cells to become allergen-specific IgE-producing plasma cells. MHC denotes a major histocompatibility complex. Allergen-specific IgE antibodies attach to high-affinity receptors on the surface of tissue- resident mast cells and circulating baso- phils. On re-exposure, the allergen binds to IgE on the surface of those cells and cross-links IgE receptors, resulting in mast-cell and basophil activation and the release of neuroactive and vasoactive mediators such as histamine and the cysteinyl leukotrienes. These elements produce the typical symptoms of allergic rhinitis. Local activation of Th2 lymphocytes by dendritic cells results in the re- lease of chemokines and cytokines that orchestrate the influx of inflammatory cells (eosinophils, basophils, neutrophils, T cells, and B cells) to the mucosa, providing more allergen targets and up-regulating the end organs of the nose (nerves, vasculature, and glands). Th2 inflammation renders the nasal mucosa more sensi - tive to allergens as well as environmental irritants. Moreover, ex- posure to allergens further stimulates the production of IgE. Generation of Nasal Symptoms on Allergen Exposure: Mediators released by mast cells and basophils can promptly activate senso- ry-nerve endings, blood vessels, and glands through specific re - ceptors. Histamine directly affects blood vessels (leading to vascu- lar permeability and plasma leakage) and sensory nerves, whereas leukotrienes are more likely to cause vasodilatation. Activation of sensory nerves leads to the generation of pruritus and various cen- tral reflexes. These include a motor reflex leading to sneezing and parasympathetic reflexes that stimulate nasal-gland secretion and produce some vasodilatation. In addition, the sympathetic drive to the erectile venous sinusoids of the nose is inhibited, allowing for vascular engorgement and obstruction of the nasal passages. In the presence of allergic inflammation, these end-organ respons - es become up- regulated and more pronounced. Sensory-nerve hyperresponsiveness is a common pathophysiological feature of allergic rhinitis.
Figure A: Sensitization
Figure B: Re-exposure
Figure C: Generation of Nasal Symptoms on Allergen Exposure
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