Pathophysiology of the inflammatory response

Airway allergic reactions enlist diverse cells and a multitude of chemical mediators that are responsible for the clinical symptoms of allergic rhinitis and asthma. Experiments in vitro and in animal models, as well as increasingly numerous studies in atopic human subjects, are revealing that an orchestrated continuum of cellular activities leading to airway allergic inflammation is set in motion in genetically predisposed individuals at the first exposure to a novel antigen. This sensitization step likely depends on differentiation of and cytokine release by T(H)2 lymphocytes. Among T(H)2-derived cytokines, IL-4 potently enhances B-lymphocyte generation of immunoglobulin E antibodies. The attachment of these antibodies to specific receptors on airway mast cells sets the stage for an acute inflammatory response on subsequent antigen exposure because IgE cross-linking by a bound antigen activates mast cells to release numerous inflammatory mediators. These mast cell-derived mediators collectively produce acute-phase clinical symptoms by enhancing vascular leak, bronchospasm, and activation of nociceptive neurons linked to parasympathetic reflexes. Simultaneously, some mast cell mediators up-regulate expression on endothelial cells of adhesion molecules for leukocytes (eosinophils, but also basophils and lymphocytes), which are key elements in the late-phase allergic response. Chemoattractant molecules released during the acute phase draw these leukocytes to airways during a relatively symptom-free recruitment phase, where they later release a plethora of cytokines and tissue-damaging proteases that herald a second wave of airway inflammatory trauma (late-phase response). The repetition of these processes, with the possible establishment in airway mucosa of memory T lymphocytes and eosinophils that are maintained by paracrine and autocrine cytokine stimulation, may account for airway hypersensitivity and chronic airway symptoms.