Airways Eosinophils as Antigen-presenting Cells in Asthma

气道嗜酸性粒细胞作为哮喘中的抗原呈递细胞

• 批准号: 7591646
• 负责人: PETER F WELLER
• 金额: $ 42.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591646
• 关键词: Abbreviations; Allergens; Allergic; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Asthma; B-Lymphocytes; Bronchoalveolar Lavage; Cell Communication; Cell physiology; Cells; Cessation of life; Chronic; Cytoplasmic Granules; Dendritic Cells; Disease; Eicosanoids; Electron Microscopy; Eotaxin; Erythrocytes; Fc Receptor; Hen Egg Lysozyme; Human; IgE; IgG Receptors; Immune; Immunization; Immunoglobulin A; Immunoglobulin G; Inflammation; Inflammation Mediators; Knock-out; Leukocytes; Leukotriene C4; Ligands; Lung; Lymphocyte; Lymphocyte antigen CD50; Lymphoid; Lymphoid Cell; Lymphoid Tissue; MHC Class II Genes; Mediating; Mediation; Mus; Myelogenous; Nature; Organ; Ovalbumin; Paratracheal; Participant; Process; Proteins; Public Health; Receptors, Antigen, B-Cell; Recruitment Activity; Regulation; Research; Respiratory System; Respiratory tract structure; Role; SLAM protein; Site; Spleen; Sputum; Staging; Structure of thyroid parafollicular cell; Synapses; T-Cell Receptor; T-Lymphocyte; TSLP gene; Testing; Thymus Gland; Transgenic Organisms; Transport Process; allergic airway disease; aluminum sulfate; base; cysteinyl-leukotriene; cytokine; eosinophil; eosinophil peroxidase; gastrointestinal; human TSLP protein; in vivo; insight; intraperitoneal; lymph nodes; novel; paracrine; programs; public health relevance; receptor; response; trafficking

DESCRIPTION (provided by applicant): Studies will investigate capabilities and mechanisms whereby eosinophils, including those recruited within airways in asthma, function as antigen-presenting cells that are of importance in propagating or modulating varied lymphocyte-dependent responses to respiratory tract encountered antigens. As antigen-presenting cells, eosinophils have distinct capabilities: First, airway eosinophils express requisite Class II MHC and lymphocyte costimulatory proteins. Second, eosinophils, like dendritic cells, function as "professional" antigen-presenting cells in expressing lymphocyte costimulatory proteins and activating unsensitized, naive T cells. Third, eosinophils, in contrast to other antigen-presenting cells, contain preformed stores of diverse cytokines that can be rapidly and selectively secreted to modulate varied lymphocyte responses. Fourth, eosinophils, like other antigen-presenting cells, utilize Fc receptor- mediated mechanisms to enhance antigen presentation by antigen-presenting cells. Eosinophil IgE, IgA and IgG receptors, together with airway allergen-specific IgE, IgA and IgG antibodies, can effectively present allergens. Fifth, airway eosinophils traffick into lymph nodes, spleen and even the thymus enabling airway antigens to be processed and transported into regional and systemic lymphoid tissues for presentation to varied lymphocytes. Sixth, eosinophils express ligands and receptors classically associated with dendritic cells, including DC-SIGN. Moreover, eosinophils can modulate B lymphocyte responses since eosinophils are critical participants in alum immunization-mediated B cell priming. Hypotheses to be tested are: that eosinophils trafficking from the airways are effective at presenting antigens to regulate, potentially differing, T lymphocyte responses in both regional and systemic lymphoid cells; that selective, restricted secretion of eosinophil cytokines mediates differential regulation of eosinophil antigen-presenting cell functions; and that eosinophils have roles in mediating the priming and responsiveness of B cells. Studies aim to investigate mechanisms by which eosinophils traffic and function as antigen-presenting cells to regulate regional and systemic T cell responses; eosinophil cytokines function in differential mediation of eosinophil antigen-presenting cell functions, and eosinophils function in B cell priming and activation. Roles for eosinophils as antigen-presenting cells in mediating allergic responses to airway antigens would provide novel insights into the characteristically chronic nature of asthma and other allergic airway diseases. PUBLIC HEALTH RELEVANCE. Asthma is an increasingly prevalent disease and a major public health problem. The research will help in understanding mechanisms that contribute to making asthma a chronic and persistent disease.

描述（由申请人提供）：研究将调查嗜酸性粒细胞（包括哮喘气道内募集的嗜酸性粒细胞）作为抗原呈递细胞的功能和机制，这些细胞在传播或调节对呼吸道遇到的抗原的各种淋巴细胞依赖性应答中具有重要作用。作为抗原呈递细胞，嗜酸性粒细胞具有独特的功能：首先，气道嗜酸性粒细胞表达必需的II类MHC和淋巴细胞共刺激蛋白。第二，嗜酸性粒细胞，像树突状细胞一样，作为“专业”抗原呈递细胞表达淋巴细胞共刺激蛋白和激活未致敏的幼稚T细胞。第三，嗜酸性粒细胞，与其他抗原呈递细胞相反，含有预先储存的不同细胞因子，可以快速和选择性地分泌，以调节不同的淋巴细胞反应。第四，嗜酸性粒细胞与其他抗原呈递细胞一样，利用Fc受体介导的机制来增强抗原呈递细胞的抗原呈递。嗜酸性粒细胞IgE、伊加和IgG受体与气道变应原特异性IgE、伊加和IgG抗体一起可有效地呈递变应原。第五，气道嗜酸性粒细胞进入淋巴结、脾脏甚至胸腺，使气道抗原能够被加工并转运到区域和全身淋巴组织中，以呈递给各种淋巴细胞。第六，嗜酸性粒细胞表达与树突细胞典型相关的配体和受体，包括DC-SIGN。此外，嗜酸性粒细胞可以调节B淋巴细胞应答，因为嗜酸性粒细胞是明矾免疫介导的B细胞引发的关键参与者。待检验的假设为：从气道运输的嗜酸性粒细胞在呈递抗原以调节局部和全身淋巴样细胞中的T淋巴细胞应答（可能是不同的）方面是有效的;嗜酸性粒细胞细胞因子的选择性、限制性分泌介导嗜酸性粒细胞抗原呈递细胞功能的差异调节;以及嗜酸性粒细胞在介导B细胞的引发和应答方面具有作用。研究旨在探讨嗜酸性粒细胞作为抗原呈递细胞运输和功能调节局部和全身T细胞应答的机制;嗜酸性粒细胞细胞因子在嗜酸性粒细胞抗原呈递细胞功能的差异介导中的功能，以及嗜酸性粒细胞在B细胞引发和活化中的功能。嗜酸性粒细胞作为抗原递呈细胞在介导对气道抗原的过敏反应中的作用将为哮喘和其他过敏性气道疾病的慢性特征提供新的见解。公共卫生相关性。哮喘是一种日益流行的疾病，也是一个主要的公共卫生问题。这项研究将有助于了解导致哮喘成为慢性和持续性疾病的机制。