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

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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.