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: 7683161
• 负责人: DOUGLAS A KUPERMAN
• 金额: $ 37.75万
• 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/7683161
• 关键词: Allergens; Allergic; 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）：分泌型 IgA (SIgA) 通常保护粘膜表面。它通过聚合免疫球蛋白受体（pIgR）转运至粘膜表面的管腔。有强有力的证据表明，SIgA 的抑制会导致过敏性疾病中粘膜免疫的失败。在最近的临床研究中，观察到哮喘患者灌洗液中 SIgA 水平降低与哮喘严重程度恶化相关。与健康对照受试者相比，我们在患有嗜酸性粒细胞过敏性气道疾病、慢性鼻窦炎伴鼻息肉 (CRSwNP) 受试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其脱颗粒。组织 IgA 的增加与鼻腔冲洗液中 SIgA 减少 3 倍相关。我们认为该机制是由于 IL-13 诱导 15-脂氧合酶-1 (15-LO-1) 所致。我们发现，IL-13 增加气道上皮细胞中 15-LO-1 及其小鼠等效物 12/15-脂氧合酶 (12/15-LO) 的表达，并且 12/15-LO 具有抑制 SIgA 的功能，并导致体内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 并将 SIgA 增加至正常水平。这可以改善保护性粘膜免疫力并限制组织嗜酸性粒细胞增多的破坏作用。该提案的一个中心假设和研究主题是 SIgA 中和气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。目标之一是测试 SIgA 系统是否正常保护气道免受粘膜表面遇到的抗原的影响，以及测试我们提出的假设，即该系统受 12/15-LO 途径的花生四烯酸代谢调节。最后，我们将检验以下假设：由于 Th2 型过敏性炎症，该保护系统的有效性较低。具体目标 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。具体目标 2. 检验 12/15-LO 表达、SIgA 产生和对实验性哮喘的易感性受 Th2 和 Th1 反应相互调节的假设。具体目标 3. 检验 SIgA 是关键免疫效应物的假设，可保护 12/15-LO-/- 小鼠免遭实验性哮喘。公共卫生相关性。我们的研究表明，在过敏性气道疾病中，抗体介导的传导气道的一线防御受到抑制。预计这将导致对肺部感染的易感性和对吸入过敏原的过敏。我们的初步研究结果表明，15-脂氧合酶-1 的诱导可能是造成这种情况的原因。因此，抑制该途径可能会增强粘膜免疫系统的保护作用。我们的研究将为支持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。