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Wise et al.

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affinity receptor Fc ε RI. Although IgE in plasma is short-lived, IgE that is receptor-bound remains attached to these cells for weeks or months. Moreover, when IgE bound to Fc ε RI cross-links with a specific allergen, it induces the release of preformed inflammatory mediators from mast cells and basophils, resulting in clinical manifestations of allergic diseases. Cytokines including IL-4 and IL-13 released from T cells and mast cells drive the differentiation of B cells into IgE-secreting plasma cells. Several studies, both in vivo and in vitro have confirmed the production of local IgE in the nasal mucosa of patients with AR. 282-284 The locally produced IgE plays a key role in ongoing inflammation by up-regulating Fc ε RI expression in mast cells. 283-285 The augmented expression of Fc ε RI allows them to bind greater numbers of IgE-antigen complexes, which in turn enhances the sensitivity of mast cells to allergen. This results in an increased production of immunomodulatory cytokines and chemical mediators, forming an important positive-feedback amplification loop involving the IgE-IgE receptor cascade, thus perpetuating ongoing inflammation. 285,286 Interestingly, the density of IgE receptors and IgE molecules in mast cells within the nasal mucosa of patients with AR have been shown to correlate with levels of serum IgE. 285 The presence of elevated levels of IgE in nasal secretions has been demonstrated in non-allergic rhinopathy as well, which potentially further highlights a significance of the IgE-IgE receptor cascade in driving the disease process of rhinitis. 287 IV.A.3. Local IgE production and local allergic rhinitis (LAR)— LAR is a regional inflammatory condition defined by local symptoms and sIgE-mediated inflammation without evidence of systemic hypersensitivity. 107,194,284,288 It is important to remember that conventional allergy testing, such as SPT and the radioallergosorbent test (RAST), only indicates sensitization (atopy), but not symptomatic allergy. While it is possible for a positive allergy skin or in vitro test result to lack clinical relevance, the opposite is also true, as a negative allergy skin or in vitro test result does not exclude regional IgE-mediated sensitivity, as in the case of LAR. 194,288-290 LAR may affect more than 47% of children and adults previously classified as NAR, 290-295 and persists throughout the years with a low rate of conversion to clinical AR. 296-298 However, LAR may evolve to the development of asthma. 296,297 Diagnosis of LAR is based on demonstration of a positive response to NPT and/or the detection of nasal sIgE and/or a positive basophil activation test (BAT) in the absence of systemic atopy. The pathophysiology of LAR is complex and not completely understood. Immunologic studies have revealed the existence of a Th2 inflammatory response in the nasal mucosa of LAR patients, 177,299-301 with positive response to NPT, 291,300-302 and local production of sIgE 177,290,299-301,303-305 and inflammatory mediators. 304,306,307 Nasal Th2 inflammatory response.: Flow cytometry studies in nasal secretions have confirmed that aeroallergen exposure induces a Th2 inflammatory response in the nasal mucosa of LAR patients with increased eosinophils, basophils, mast cells, CD3+, and CD4+ T cells. 300,301 NPT studies have demonstrated the existence of characteristic immediate/ early and late-phases of the allergic response in LAR patients with local production of sIgE, mast cell, and eosinophil activation, with mucosal secretion of tryptase and ECP. 306,307 A

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