15-lipoxygenase regulation of mucosal immunity in allergic airways disease

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DESCRIPTION (provided by applicant): Secretory IgA (SIgA) normally protects mucosal surfaces. It is transported to the lumen of mucosal surfaces by the polymeric immunoglobulin receptor (pIgR). There is strong evidence that suppression of SIgA produces a failure of mucosal immunity in allergic disease. In recent clinical studies, it was observed that decreased levels of SIgA in lavage fluid from subjects with asthma correlated with worsening asthma severity. In comparison to healthy control subjects, we detected approximately 6-fold increases of IgA in nasal tissue biopsies from subjects with the eosinophilic allergic airways disease, chronic rhinosinusitis with nasal polyps (CRSwNP). This is concerning because IgA binding to eosinophils induces their degranulation. Increases in tissue IgA were associated with 3-fold decreases of SIgA in nasal washings. We believe the mechanism is due to IL-13 induction of 15-lipoxygenase-1 (15-LO-1). We show that IL-13 increases expression of 15-LO-1 and its mouse equivalent, 12/15-lipoxygenase (12/15-LO), in airway epithelial cells and that 12/15-LO functions to inhibit SIgA and causes increased susceptibility to experimental asthma in vivo. Inhibition of 15-LO-1 might help to lower tissue IgA and increase SIgA to normal levels. This could provide improved protective mucosal immunity and limit the damaging effects of tissue eosinophilia. A central hypothesis and topic of investigation of this proposal is that SIgA neutralizes allergen at the site of exposure in the airways and thereby prevents further uptake of allergen by dendritic cells and activation of immune and inflammatory responses. One of the goals is to test whether the SIgA system normally protects the airways from exposure to antigens encountered at mucosal surfaces as well as to test hypotheses that we have developed that this system is regulated by the metabolism of arachidonic acid by the 12/15-LO pathway. Finally, we will test the hypothesis that this protective system is less effective as a consequence of Th2-type allergic inflammation. Specific Aim 1. To determine the role of 12/15-LO in regulation of mucosal B-cell activation, SIgA production and susceptibility to experimental asthma. Specific Aim 2. To test the hypothesis that 12/15-LO expression, SIgA production, and susceptibility to experimental asthma are reciprocally regulated by Th2 and Th1 responses. Specific Aim 3. To test the hypothesis that SIgA is the key immunological effector that confers protection from experimental asthma in 12/15-LO-/- mice. PUBLIC HEALTH RELEVANCE. Our studies indicate that there is suppression of the antibody-mediated first-line defense of the conducting airways in allergic airways disease. This would be predicted to result in susceptibility to pulmonary infections and hypersensitivity to inhaled allergens. Our preliminary findings indicate that induction of 15-lipoxygenase-1 may be responsible. Therefore, inhibition of this pathway may augment the protective role of the mucosal immune system. Our studies will provide valuable information supporting the goal of the National Institutes of Health to prevent disease and promote health.