An IgE-dependent allergic reaction is characterized by an early-phase and a late-phase reaction (Fig. 1). The early-phase reaction involves the release of histamine and other proinflammatory mediators. In the airways these lead, within seconds or minutes, to vasodilatation, increased permeability, and symptoms of nasal discharge, sneezing, and bronchoconstriction (1). During the early-phase reaction, mast cells release histamine and other preformed elements such as enzymes, hydrolases, and proteoglycans, and also release proinflammatory mediators such as prostaglandins (e.g. PGD2), leukotrienes, platelet-activating factor, bradykinin, and cytokines (e.g. tumour necrosis factor-α and interleukins IL-4, IL-5, IL-6, IL-10, and IL-13) (2). Proinflammatory mediators initiate a complex network of inflammatory phenomena involving adhesion molecules, Th2 T lymphocytes (which mainly release IL-4, IL-5, and IL-13), cytokines, and mediators (Fig. 2). These result in the late and ongoing allergic symptoms of nasal congestion, asthma, and urticaria. For an exhaustive review of the IgE-dependent allergy cascade, the reader is referred to the recent publication of the Allergic Rhinitis and Its Impact on Asthma (ARIA) Workshop Group (2).
Figure 1. The IgE-dependent allergy cascade. APC, antigen-presenting cell; B, B lymphocyte; FcεRI, high-affinity receptor for IgE; GM-CSF, granulocyte monocyte colony-stimulating factor; IL, interleukin; PAF, platelet-activating factor; Th2, Th2 T lymphocyte; VCAM-1, vascular cellular adhesion molecule-1.
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Figure 2. The allergic reaction. APC, antigen-presenting cell; B, B lymphocyte; Eos, eosinophil; ECP, eosinophil cationic protein; EDX, eosinophil-derived neurotoxin; Fibro, fibroblast; IL, interleukin; iNOS, inducible nitric oxide synthase; ITS, specific immunotherapy; LT, leukotriene; MBP, major basic protein; Neu, neutrophil; Th1, Th1 T lymphocyte; Th2, Th2 T lymphocyte; VCAM-1, vascular cellular adhesion molecule-1.
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One of the earliest and most important actions of proinflammatory effects caused by mast cells is to up-regulate or cause the de novo expression of adhesion molecules on the surface of endothelial cells (selectins) and epithelial cells (integrins). Adhesion molecules are involved in the recruitment of inflammatory cells (eosinophils, basophils, and neutrophils) from the circulation to the site of the inflammatory reaction. Specific adhesion molecules favour the tether/roll of inflammatory cells towards the epithelium (e.g. vascular cellular adhesion molecule-1 (VCAM-1), P-selectin, and L-selectin), the firm arrest of inflammatory cells to the epithelium (e.g. CD18 integrin, intercellular adhesion molecule-1 (ICAM-1), and VCAM-1), and diapedesis (migration) through the epithelium (3). Experimental nasal, conjunctival, and bronchial data indicate that inflammatory cells begin to migrate to the mucosa approximately 30 min after specific challenge, continue to increase during the following 24 h, and then slowly subside (4–7). However, up-regulation of expression of the ICAM-1 molecule is evident on the conjunctival and nasal epithelium of allergic patients, even when they are asymptomatic (8).
Persistent up-regulation of ICAM-1 expression offers a theoretical mechanism for the minimal persistent inflammation that continues in the absence of symptoms when a subthreshold exposure to the allergen persists (8,9). It also suggests a mechanism for the exacerbation of asthma in children during upper respiratory viral infection (10,11); the ICAM-1 molecule is the major receptor for human rhinoviruses (12), which in turn is the main cause of upper respiratory tract viral infections in children.