15-lipoxygenase regulation of mucosal immunity in allergic airways disease

描述(申请人提供)：分泌型免疫球蛋白A(SIgA)通常保护粘膜表面。它通过聚合免疫球蛋白受体(PIgR)转运到粘膜表面的管腔。有强有力的证据表明，在变态反应性疾病中抑制SIgA会导致粘膜免疫失败。在最近的临床研究中，人们观察到哮喘患者灌洗液中SIgA水平的降低与哮喘严重程度的恶化有关。与健康对照组相比，我们检测到患有嗜酸性过敏性呼吸道疾病-慢性鼻窦炎鼻息肉(CRSwNP)的患者鼻组织活检中的IgA增加了约6倍。这是令人担忧的，因为IgA与嗜酸性粒细胞结合会导致其脱颗粒。组织中IgA的增加与鼻洗液中SIgA的3倍减少有关。我们认为其机制可能与IL-13诱导15-脂氧合酶-1(15-LO-1)有关。我们发现，IL-13增加了15-LO-1及其相当于小鼠的12/15-脂氧合酶(12/15-LO)在呼吸道上皮细胞中的表达，并且12/15-LO具有抑制SIgA的作用，并导致体内对实验性哮喘的易感性增加。抑制15-LO-1可能有助于降低组织中的IgA，使SIgA恢复到正常水平。这可以提供更好的保护性粘膜免疫力，并限制组织嗜酸性粒细胞增多症的破坏性影响。关于这一提议的一个中心假设和研究主题是，SIgA中和呼吸道暴露部位的过敏原，从而防止树突状细胞进一步摄取过敏原，并激活免疫和炎症反应。目的之一是测试SIgA系统是否正常保护呼吸道免受黏膜表面遇到的抗原的影响，并验证我们提出的假设，即该系统受12/15-LO途径的花生四烯酸代谢调节。最后，我们将测试这一保护系统由于Th2型过敏性炎症而不那么有效的假设。具体目的1.确定12/15-LO在调节粘膜B细胞活化、SIgA产生和实验性哮喘易感性中的作用。具体目的2.验证12/15-LO表达、SIgA产生和实验性哮喘易感性受Th2和Th1应答相互调节的假说。具体目的3.在12/15-LO-/-小鼠中验证SIgA是预防实验性哮喘的关键免疫效应因子的假说。与公共卫生相关。我们的研究表明，在过敏性呼吸道疾病中，抗体介导的传导气道一线防御受到抑制。据预测，这会导致肺部感染的易感性和对吸入性过敏原的过敏。我们的初步发现表明，15-脂氧合酶-1的诱导可能是原因之一。因此，抑制这一途径可能会增强粘膜免疫系统的保护作用。我们的研究将提供有价值的信息，支持国家卫生研究院预防疾病和促进健康的目标。

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.