Mechanismen der Toll-like Rezeptor (TLR)-vermittelten Entstehung und Inhibition von Allergischen Atemwegserkrankungen

点击翻译按钮获取中文摘要

Asthma is a chronic inflammatory airway disease with a dramatically increasing prevalence in Western industrialized countries. The Hygiene hypothesis predicts that bacterial infections should inhibit the development of asthma. However, there is evidence that respiratory infections as well as exposure towards microbial compounds may trigger airway sensitization. We have obtained evidence that infection of mice with Chlamydia pneumoniae, a pathogen repeatedly associated with the pathogenesis of asthma, induces sensitization of mice towards an inert antigen, resulting in eosinophilic airway inflammation mimicking asthma when the antigen is encountered again. Airway sensitization is dependent on severity and stage of respiratory infection, with mild inflammation at early stages favoring the process. Innate immune responses are crucially involved, since airway sensitization is mediated by dendritic cells (DCs) and is dependent on Toll-like receptor (TLR)-activation. Here, I want to further elucidate the mechanisms by which innate immune responses can promote airway sensitization towards inert antigens. Furthermore, I want to investigate the mechanisms by which severe inflammation, caused by infection or TLR-stimulation, can inhibit airway sensitization. Finally, I want to test the hypothesis that innate immune activation, mediated by pathogens or by isolated microbial TLR-ligands, can inhibit allergic airway inflammation through the induction of immunotolerance via antigen-specific regulatory T-cells, depending on timing and dose of the stimulus.