Systems-immunology as a tool to identify mechanisms of allergy development

过敏性哮喘的特点是慢性炎症反应。人们对其潜在机制知之甚少。目前的治疗策略只对患者的过敏性疾病症状进行了不充分的治疗，缺乏预防策略。目前尚不清楚为什么内源性免疫调节机制无法阻止过敏反应的发展和稳定。对这些细胞机制和因素的识别可能有助于为过敏患者设计新的治疗方法，获得生物标记物，以及制定预防过敏性疾病发展的策略。近年来，包括microRNAs在内的基因转录后调控机制在多种疾病中得到了描述，并与疾病的发生和严重程度有关。然而，由于单个microRNA可以靶向数百个蛋白质编码基因，因此很难识别与疾病相关的miRNA介导的基因调控。为了阐明这些机制，将使用一种新的整合系统-免疫学方法。这个算法识别了由miRNAs在细胞(相互作用体)的一整套分子相互作用中引起的关键基因调控变化。它还通过应用基于网络的优先算法来估计和权衡miRNA活动对互动组的净影响。利用这种方法，可以识别与疾病相关的microRNA-基因-相互作用、microRNA网络以及受调控的途径。该算法将应用于从过敏性呼吸道炎症小鼠模型中分离的免疫细胞的基因表达数据，以确定解释内源性调节机制失败的机制。这些可能成为开发治疗和预防过敏性疾病的新概念的潜在候选者。

Allergic asthma is characterized by a chronic inflammatory response. The underlying mechanisms are poorly understood. Current treatment strategies only insufficiently treat symptoms of allergic diseases in patients and preventive strategies are missing. It is still unclear why endogenous immune-regulatory mechanisms are unable to prevent the development and stabilization of the allergic response. The identification of these cellular mechanisms and factors might help to design new therapies for allergic patients, to derive biomarkers as well as to develop strategies to prevent the development of allergic diseases. In recent years, post-transcriptional mechanisms of gene regulation, including microRNAs, are described in a variety of diseases and associated with development as well as severity of disease. However, since a single microRNA can target several hundred protein coding genes, it is difficult to identify disease-relevant miRNA-mediated gene regulation. To elucidate these mechanisms, a novel integrative systems-immunology approach will be used. This algorithm identifies key gene-regulatory alterations evoked by miRNAs in the whole set of molecular interactions in a cell (interactome). It further estimates and weighs the net consequences of miRNA activity on the interactome by applying a network-based prioritization algorithm. With this approach disease-relevant microRNA-gene-interactions, microRNA networks as well as regulated pathways can be identified. This algorithm will be applied on gene expression data of immune cells isolated from a mouse model of allergic airway inflammation to identify mechanisms explaining the failure of endogenous regulatory mechanisms. These might serve as potential candidates for the development of novel concepts to treat and prevent allergic diseases.