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Inflammatory Nature of Allergic Rhinitis: Implication for Future Therapies: Pathophysiology



From a morphologic standpoint, the inflammatory nature of allergic rhinitis is readily apparent by the characteristic presence of basophilic and eosinophilic cells in nasal secretions, accompanied by mast cell and eosinophil infiltration of the epithelium and an increase in mucosal antigen-presenting cells, activated T lymphocytes, and upregulated endothelial expression of adhesion molecules.[5] The importance of the inflammatory nature of allergic rhinitis is reflected by its definition as "inflammation of the membranes lining the nose and is characterized by nasal congestion, rhinorrhea, sneezing, itching of the nose, and/or postnasal drainage."[3] This definition was derived by the Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology in 1998.[4]

Inflammatory Cascade

The allergic inflammatory cascade is often characterized as having 3 components including sensitization followed by an early- and late-phase response, which can be thought of in a sequential fashion.[6] Although the temporal picture is simple, it should be recognized that all pathways are operative (to a greater or lesser degree) simultaneously with a complex interaction among a variety of cells, mediators, and cytokines. It is within these pathways that targets for immunomodulation offer the greatest opportunities for pharmacologic interventions to prevent or ameliorate the signs and symptoms of allergic rhinitis.

Sensitization to allergen is the fundamental event leading to future amnestic inflammatory responses responsible for the symptoms of allergic rhinitis. Antigen processing, via antigen-presenting cells such as dendritic cells, results in T-cell activation and elaboration of specific cytokines, including interleukin (IL)-4, IL-5, IL-9, IL-13, and granulocyte macrophage colony-stimulating factor (GM-CSF). Not only are these cytokines proinflammatory themselves, but their subsequent induction of isotype switching and specific IgE production from B cells also is a critical step in the allergic cascade. The resultant antigen-specific IgE will bind through its high-affinity receptor to effector cells, most notably mast cells and basophils.

It is known that within minutes of allergen exposure, sensitized mast cells will release preformed and newly synthesized mediators, including histamine, cysteinyl leukotrienes, prostaglandins, and platelet-activating factor. This event is followed immediately by sneezing, itching, and rhinorrhea, characteristic of the early-phase response of an allergic rhinitis. Accompanying these early events is the attraction of other inflammatory cells to the nasal mucosa, including basophils, eosinophils, neutrophils, newly synthesized mast cells, and mononuclear cells. Subsequent to the arrival of these other inflammatory cells, release of additional mediators creates a sustained inflammatory reaction with continued inflammatory cell recruitment and constitutes the late-phase response of allergic rhinitis characterized by nasal congestion and mucus hypersecretion.

IgE and Cross-Linking

Initial triggering of sensitized mast cells is accomplished through membrane perturbation when 2 molecules of specific IgE (bound to the surface of mast cells through the high-affinity receptor) are cross-linked by corresponding recognized antigen. Cross-linking bound IgE results in immediate release of preformed mediators such as histamine and the release of newly synthesized mediators (generated through the arachidonic acid pathway) as well as cytokines such as tumor necrosis factor-alpha (TNF-a), IL-4, and IL-5. IL-5 is thought to be a cytokine crucial to the release and growth of eosinophils and their precursors in blood and bone marrow. Subsequent upregulation of adhesion molecule expression on the vascular endothelium includes E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, which permits migration of leukocytes under chemotactic stimuli to the mucosal environment. For example, bone marrow-derived eosinophils migrate to the site of allergic inflammation, releasing their own unique granular-based products and cytokines such as major basic protein, eosinophilic cationic protein (ECP), platelet-activating factor, and a variety of cytokines, including IL-3 and IL-5. The cysteinyl-leukotrienes are also released into the area by eosinophils. This sets the stage for a more chronic inflammatory response leading to the more protracted and refractory symptom of nasal congestion, which not only is the most bothersome symptom to allergy sufferers, but also is the most difficult to treat pharmacologically.

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