Allergic Networks Regulating Eosinophilia

Although asthma is a disease of complex etiology, it is becoming increasingly apparent that inflammation of the airway mucosa is a major factor predisposing to the clinical manifestations of this disease (1‐4). The localization and activation of specific inflammatory cells within the lung correlates with the temporal phases of airway obstruction and enhanced bronchial responsiveness to spasmogenic stimuli. In particular, immunoglobulin (Ig) E‐dependent activation of mast cells and CD4 1 T-helper type 2 (Th2) cell‐regulated eosinophilia are thought to be key mediators of the early- and late-phase responses of allergic asthma, respectively (1‐5). Th2 cells and eosinophilia are also predominant features of inflammatory infiltrates during exacerbations of nonallergic asthma (6). Notably, both clinical and experimental observations show a strong correlation between the presence of eosinophils and their products in the airways, disease severity, and the development of airway hyperreactivity (4, 5). Although there is a strong correlation between eosinophilic inflammation of the bronchial mucosa and disease severity, the specific pathophysiologic mechanisms that predispose to the clinical manifestations of asthma have not been fully delineated. Recently, murine models of allergic lung disease have been employed in attempts to provide insights into the complex inflammatory processes of the asthmatic airways. Although these models are only representative of the immunopathologic processes underlying asthma, they have provided us with an important tool to help identify the potential contribution of individual inflammatory molecules and cells to specific pathophysiologic processes that are hallmarks of this disorder. Notably, these models have provided corroborative evidence of the central importance of Th2-cells and -cytokines and eosinophilia to the etiology of asthma (7‐9). They have also identified the importance of specific chemokines and adhesion systems for leukocyte migration to the allergic lung (10, 11). Collectively, murine models of asthma have demonstrated that inflammation of the airways plays a central role in disease pathogenesis. Furthermore, like the human condition, pathogenic mechanisms are complex with multiple pathways regulating the development of the asthma phenotype (11‐23). Notably, allergic disease of the lung in mouse models occurs independently of the archetypal Th2-cell differentiation factor, interleukin (IL)-4, IgE, B cells, and mast cells, suggesting the existence of compensatory pathways (8, 9, 16, 17, 20, 24). In the absence of these key regulators of allergic disease, a residual Th2-driven airways eosinophilia is a predominant feature of the inflammatory response after allergen provocation (12, 16, 20, 25). Although the recruitment of eosinophils to the air