Project

Asthma; Epithelial cells; Innate immune response; Inflammasome; Epigenetic; Cytokines; Tight Junctions; T cells; Atopic dermatitis; Barrier

Lead
Mit einem epidemischen Anstieg in den letzten 60 Jahren, betreffen allergische Erkrankungen über 1 Mrd. Menschen weltweit, mit steigender Prävalenz auf 4 Mrd. bis 2050.
Lay summary
In der Schweiz leiden rund 1.7 Mio. Menschen an einer allergischen Krankheit. Ca. 5-10% dieser Krankheiten mit schwerer Form können zum Tode führen. Wir konnten zusammen mit anderen beweisen, dass Defekte in der Epithelbarriere der Tight Junctions eine wichtige Rolle in der Pathogenese dieser Krankheiten spielt. Man hat zeigen können, dass die Barrierefunktion von Lungenepithelzellen von Asthmatikern, von Epithelzellen in Stirn- sowie Nebenhöhlen bei Patienten mit chronischer Rhinosinusitis und von Hautzellen bei atopischer Dermatitis beschädigt und undicht ist. Allergene, bakterielle Toxine und andere Stoffe können so das undichte Epithel durchdringen und dort womöglich die Abwehrzellen aktivieren und zu schwerer chronischer Entzündung führen. Diese Studie konzentriert sich auf die Regulierung der Epithelbarriere und ihre zellulären sowie molekularen Mechanismen. Die Untersuchungen werden parallel bei Asthma und atopischer Dermatitis geführt und konzentrieren sich besonders auf in vivo relevante Erkenntnisse, die aus primären humanen Zellen und Biopsien sowie aus Mausmodellen gewonnen werden. Oberstes Ziel dieser Studie ist, neue Wege für Prävention und Behandlung von Asthma und atopischer Dermatitis, um die individuelle Belastung der Patienten und ihrer Familien zu mindern. Diese beiden allergischen Erkrankungen betreffen fast die Hälfte der Bevölkerung weltweit und verursachen sehr hohe Gesundheitskosten. Diese Studie wird einen weiterreichenden Einfluss auch auf andere Disziplinen der Human- und Tiermedizin haben.

Direct link to Lay Summary

Last update: 05.10.2017

Natural persons

Self-organised

Self-organised

Title	Year

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Burden of Allergic Diseases: With an epidemic rise during the last 60 years, allergic diseases are affecting the lives of more than one billion people worldwide, and their prevalence is expected to reach up to 4 billion in 2050. Currently, 300 million people (4.2%) suffer from asthma, 500 million (6.5%) from atopic dermatitis (AD), 900 million (12 %) from allergic rhinitis) and 700 million (9%) from food allergy worldwide. The prevalence of these four allergic diseases is approximately 1.7 million 22% in Switzerland. Atopic dermatitis is the most prevalent chronic disease in childhood. Asthma represents one of the highest costs to health care system. Allergic rhinitis is the number one disease for job absenteeism (missing work days) and presenteeism (being on the job, but not fully functioning because of disease). Approximately, 5-10% of all of these diseases present with severe forms and can cause deaths. It was recently shown by us and others that epithelial tight junction barrier defect plays an important role in the pathogenesis of these diseases.Epithelial barrier function: of asthmatic bronchial epithelial cells, sinus epithelial cells in chronic rhinosinusitis and skin keratinocytes in atopic dermatitis have been demonstrated to be defective and leaky. Allergens, bacterial toxins and other particles are able to penetrate the leaky epithelium, where they may activate the immune system cells leading to severe chronic inflammation. Epithelial tight junctions (TJ) are responsible for the regulation of paracellular flux and epithelial impermeability and can be considered as gatekeepers that could contribute both to aggravation of inflammation-related tissue damage or resolution of inflammation via drainage towards out side of the affected tissues. This study focuses on the regulation of particularly TJ barrier by epigenetic mechanisms and inflammasome.Planned experiments: According to our strong preliminary data, we hypothesize here that “epithelial tight junction barrier is epigenetically controlled” and “epithelial barrier leakiness is affected by inflammasome and both TJ barrier and inflammasome are epigenetically regulated”. We will perform this research in asthma and atopic dermatitis in parallel and particularly focus on in vivo relevant findings that will be obtained from direct human primary cells and biopsies as well as mouse models. We aim to demonstrate epigenetic mechanisms of bronchial and skin epithelial barrier leakiness in different endotypes and phenotypes of asthma and atopic dermatitis and bring a new perspective from bench to patient side. We will use several important and in vivo relevant stimulants to study the “barrier”, “epigenetics” and “inflammasome” triangle. They will be house dust mite, human rhinovirus, commercial detergents and their surfactants, and CpG oligonucleotides. In this way, we will be able to investigate barrier damaging and recovering as well as inflammasome-activating and -nonactivating stimulants.Impact and innovative potential: The ultimate aim of this research is to find out novel preventive and treatment ways for two major allergic diseases, asthma and atopic dermatitis to decrease the individual burden of the patients and their families, which affects almost half of the World’s population and extremely high health care costs. Our research includes disease endo and phenotyping concepts and opens a new window for a precision medicine approach to barrier leakiness, such as the establishment of leaky barrier endotype. Many aspects of this research will find broader impact in other disciplines of human and veterinary medicine, because similar mechanisms of epithelial barrier dysregulation play roles in other diseases such as chronic rhinosinusitis, COPD and inflammatory bowel disease. In addition, epigenetic regulation of inflammasome activation thresholds has a link to essentially all inflammatory diseases.