15-lipoxygenase regulation of mucosal immunity in allergic airways disease

15-脂氧合酶对过敏性气道疾病粘膜免疫的调节

• 批准号: 7911697
• 负责人: DOUGLAS A KUPERMAN
• 金额: $ 37.37万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-09 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911697
• 关键词: Allergens; Allergic Disease; Allergic inflammation; Antibody Suppression; Antigens; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Asthma; B-Cell Activation; B-Lymphocytes; Binding; Biopsy; Bone Marrow; Breathing; Breeding; Cells; Clinical Research; Cytosine deaminase; Data; Dendritic cell activation; Development; Disease; Elements; Employee Strikes; Environment; Eosinophilia; Epithelial; Epithelial Cells; Epithelium; Event; Exposure to; Extrinsic asthma; Failure; Fc Receptor; Goals; Health; Hematopoietic; Hypersensitivity; Immune; Immune system; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunoglobulins; In Situ Hybridization; In Vitro; Infection; Inflammation; Inflammatory Response; Interleukin-13; Investigation; Irrigation; Lipoxygenase 1; Liquid substance; Location; Lung; Mediating; Metabolism; Modeling; Molecular; Mucosal Immunity; Mus; Nasal Lavage Fluid; Nasal Polyps; Nose; Orthologous Gene; Pathway interactions; Patients; Phenotype; Play; Polymeric Immunoglobulin Receptors; Predisposition; Production; Publishing; Regulation; Research; Role; Secondary to; Secretory Immunoglobulin A; Severities; Site; Specificity; Surface; System; Testing; Th2 Cells; Tissues; Transcript; United States National Institutes of Health; Virus; airway epithelium; allergic airway disease; antigen challenge; chronic rhinosinusitis; eosinophil; improved; in vivo; macrophage; novel strategies; prevent; public health relevance; response; uptake

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.

描述（由申请人提供）：分泌IgA （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，在过敏性疾病中，SIgA的抑制会导致粘膜免疫的失败。在最近的临床研究中，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，我们在嗜酸性粒细胞过敏性气道疾病、慢性鼻窦炎伴鼻息肉（CRSwNP）患者的鼻组织活检中检测到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诱导它们的脱颗粒。洗鼻液中组织IgA升高与SIgA降低3倍相关。我们认为其机制是由于IL-13诱导15-脂氧合酶-1 （15-LO-1）。我们发现IL-13增加了15-LO-1及其小鼠等效物12/15-脂氧合酶（12/15-LO）在气道上皮细胞中的表达，并且12/15-LO具有抑制SIgA的功能，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IgA并使SIgA升高至正常水平。这可以提供更好的保护性粘膜免疫和限制组织嗜酸性粒细胞的破坏作用。本研究的中心假设和研究主题是SIgA在气道暴露部位中和过敏原，从而阻止树突状细胞进一步摄取过敏原并激活免疫和炎症反应。其中一个目标是测试SIgA系统是否正常地保护气道免受粘膜表面遇到的抗原的暴露，以及测试我们提出的假设，即该系统是由花生四烯酸代谢通过12/15-LO途径调节的。最后，我们将验证这种保护系统由于th2型过敏性炎症而效果较差的假设。具体目标探讨12/15-LO在调节黏膜b细胞活化、SIgA产生及实验性哮喘易感性中的作用。具体目标2。为了验证12/15-LO表达、SIgA产生和实验性哮喘易感性受Th2和Th1反应相互调节的假设。具体目标3。为了验证SIgA是12/15-LO-/-小鼠抗实验性哮喘的关键免疫效应物的假设。公共卫生相关性。我们的研究表明，在变应性气道疾病中，抗体介导的传导气道一线防御受到抑制。这将导致对肺部感染的易感性和对吸入过敏原的超敏反应。我们的初步研究结果表明，15-脂氧合酶-1的诱导可能与此有关。因此，抑制这一途径可能增强粘膜免疫系统的保护作用。我们的研究将为美国国立卫生研究院预防疾病和促进健康的目标提供有价值的信息。