Airways Eosinophils as Antigen-presenting Cells in Asthma

描述（由申请人提供）：研究将调查嗜酸性粒细胞的能力和机制，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，在传播或调节呼吸道遇到抗原的各种淋巴细胞依赖性反应中发挥重要作用。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。其次，嗜酸性粒细胞，像树突状细胞一样，在表达淋巴细胞共刺激蛋白和激活未致敏的幼稚T细胞方面发挥“专业”抗原提呈细胞的作用。第三，与其他抗原呈递细胞不同，嗜酸性粒细胞含有预先形成的多种细胞因子，这些细胞因子可以快速和选择性地分泌，以调节各种淋巴细胞的反应。第四，嗜酸性粒细胞和其他抗原提呈细胞一样，利用Fc受体介导的机制增强抗原提呈细胞的抗原提呈。嗜酸性粒细胞IgE、IgA和IgG受体与气道过敏原特异性IgE、IgA和IgG抗体一起，可有效呈递过敏原。第五，气道嗜酸性粒细胞运输到淋巴结、脾脏甚至胸腺，使气道抗原被加工并运输到局部和全身淋巴组织，呈递给各种淋巴细胞。第六，嗜酸性粒细胞表达与树突状细胞相关的配体和受体，包括DC-SIGN。此外，嗜酸性粒细胞可以调节B淋巴细胞反应，因为嗜酸性粒细胞是明矾免疫介导的B细胞启动的关键参与者。有待验证的假设是：从气道运输的嗜酸性粒细胞有效地呈递抗原，以调节局部和全身淋巴样细胞的T淋巴细胞反应（可能存在差异）；嗜酸性粒细胞细胞因子的选择性、限制性分泌介导了嗜酸性粒细胞抗原呈递细胞功能的差异调节；嗜酸性粒细胞在介导B细胞的启动和反应中起作用。研究的目的是研究嗜酸性粒细胞作为抗原呈递细胞的转运和功能调节区域和全身T细胞反应的机制；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调解中起作用，嗜酸性粒细胞在B细胞的启动和激活中起作用。嗜酸性粒细胞作为抗原呈递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特征性慢性本质提供新的见解。公共卫生相关性。哮喘是一种越来越普遍的疾病，也是一个主要的公共卫生问题。这项研究将有助于了解使哮喘成为慢性和持续性疾病的机制。

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.