Role of CD97/ADGRE5 in allergic asthma

我们的建议的中心目标是阐明CD 97/ADGRE 5在哮喘的发展和维持中的作用，哮喘是一个相当大的公共卫生问题，患病率不断上升。过敏性哮喘是由抗原呈递细胞通过T细胞受体和辅助分子激活幼稚的CD 4 T细胞所传递的信号引发的对无害过敏原的不适当的T辅助细胞2（Th 2）介导的免疫应答。CD 97是一种强烈存在于免疫细胞中的粘附G蛋白偶联受体（GPCR），与其配体CD 55一起作为共刺激分子和幼稚CD 4 + T细胞的激活剂发挥作用。它是嗜中性粒细胞迁移和宿主免疫防御的重要介质，与类风湿性关节炎和多发性硬化症有关，但迄今为止还没有关于CD 97参与哮喘的信息。因此，我们将使用Cd 97缺陷（Cd 97-/-）和Cd 97-/-嵌合小鼠在各种过敏性哮喘模型中表征CD 97在哮喘病理生理学中的作用。我们自己的初步数据显示，CD 97丢失后急性哮喘明显恶化。我们将进一步研究应用已建立的CD 97抗体（在肺中富集）对小鼠哮喘发展的影响。为了阐明导致Cd 97-/-和CD 97抗体治疗小鼠哮喘调节作用的潜在机制，我们将应用细胞培养和体内过继细胞转移方法。最后，我们将使用Cd 55-/-和Cd 55-/-/Cd 97-/-嵌合小鼠评估配体CD 55及其与CD 97的相互作用在哮喘发展中的作用。我们项目的结果不仅将为CD 97在哮喘病理生理学中的功能提供新的见解，而且还可能为过敏性免疫疾病的干预提供新的策略。

The central aim of our proposal is to elucidate the role of CD97/ADGRE5 in the development and maintenance of asthma, a considerable public health problem with increasing prevalence. Allergic asthma is an inappropriate T helper cell 2 (Th2)-mediated immune response to harmless allergens which is initiated by signals delivered by antigen presenting cells which activate naïve CD4 T-cells via the T-cell receptor and accessory molecules. CD97, an adhesion G protein-coupled receptor (GPCR) strongly present in immune cells, acts with its ligand CD55 as a costimulatory molecule and activator of naïve CD4+ T-cells. It is an important mediator of neutrophilic migration and host immune defense and is linked to rheumatoid arthritis and multiple sclerosis, but there is no information on the involvement of CD97 in asthma so far. Thus, we will characterize the role of CD97 in asthma pathophysiology in various models of allergic asthma using Cd97-deficient (Cd97-/-) and Cd97-/- chimeric mice. Our own initial data have revealed an obvious worsening of acute asthma after loss of CD97. We will further investigate the impact of the application of an established CD97 antibody, which enriches in the lung, on murine asthma development. To elucidate the underlying mechanisms leading to the asthma-modulating effects in Cd97-/- and CD97 antibody-treated mice, we will apply cell culture and in-vivo adoptive cell transfer methods. Finally, we will evaluate the role of the ligand CD55 and its interaction with CD97 in asthma development using Cd55-/- and Cd55-/-/Cd97-/- chimeric mice. The results of our project will not only provide new insights in the function of CD97 in asthma pathophysiology but may also lead to novel strategies for interventions to face allergic immune diseases.