The study of genetic, immunologic and microbiologic factors in the etiopathogenesis of Crohns disease and ulcerative colitis.

The chronic idiopathic inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis are disabling diseases of the intestine occurring mostly in young patients and lead often to a greatly decreased quality of life. These diseases are believed to be the consequence of an inappropriate reaction of the mucosal immune system towards the bacterial community in the gut occurring in a genetically susceptible host. In the previous years, our group made important progress in unravelling the pathogenesis of IBD by studying each of the three main factors contributing: genetic susceptibility, immune dysregulation and intestinal microbiota and by integrating these into one pathogenic IBD model. The current proposal aims at further expanding on our recent findings for the different aspects of disease pathogenesis, we will search for one or more additional genes or copy number variations (CNVs) involved in IBD by fine mapping of candidate regions on chromosome 14 and regions identified by previous whole genome scans and by performing a CNV scan on a genome wide level. Given the recently demonstrated importance of the IL12/IL23/Th17 axis, we will study the role of IL23 and related cytokines in IBD and in the response to biological therapies and will investigate molecular mechanisms by which anti-TNF agents promote the generation and function of Tregs. We will further explore the antimicrobial seroreactivity in IBD patients, identify the target antigens for markers as pANCA and PAB and try to isolate bacterial sequences responsible for driving the inflammation. We also will explore how the proportion of identified bacteria in the gut of IBD patients may be modified e.g. by administration of pre-or probiotics, and whether these bacteria induce specific cytokine profiles by interaction with immune cells in vitro. Finally, by combining the information from serology, genetics and mucosal expression profiles, we will study if our findings can be translated to clinical applications e.g. in the prediction of disease evolution over time.

Keywords:Crohns disease