Genetic defects and immune dysregulation in patients with early onset inflammatory bowel disease

Keywords: Immunology & Infectious Disease; Genetics & Genomics; Immunodeficiency
Inflammatory bowel disease (IBD) encompasses two major diseases Crohn's disease and ulcerative colitis. A subgroup of children with very early-onset IBD presents with a severe phenotype, is non-responsive to conventional therapy and needs early surgery. Several monogenic disorders can present as very early onset IBD. This includes several forms of immunodeficiency or defects in bacterial handling as well as defects in immune regulation. We investigate children with very early onset of intestinal inflammation using whole genome or whole exome sequencing to discover novel high impact genes and analyse the involved signaling pathways in vitro, in situ and in vivo. We like to understand the pathogenesis of rare "orphan" diseases to develop better treatment options for those disorders and improve understanding of pathogenic mechanisms of IBD as a whole.
A common pathomechanism for multiple immune disorders that present with intestinal inflammation is a defect in bacterial handling by macrophages caused by defective autophagy. We therefore study how genetic defects that affect key checkpoints in bacterial recognition (such as NOD2 or XIAP) and autophagolysosome maturation (such as Niemann Pick Type C caused by NPC1 defects or Chronic granulomatous disease) cause a hyper-inflammatory response. Mapping of the functional checkpoints that are affected by common genetic variants and rare defects will allow to understand basic biology and help to develop novel autophagy inducing therapies.
Training opportunities include both basic immunology and translational research with close link to national and international pediatric gastroenterology departments. The project will have close link to the COLORS in IBD project aiming to understand genetic defects in children with very early onset of inflammatory bowel disease. Laboratory techniques include analysis of next generation sequencing data (exome and genome sequencing), flow cytometric assays, T cell culture and differentiation, macrophage infection models, proteomics, laser scanning and laser microdissection microscopy. We culture primary immune cells assess bacterial recognition and handling pathways. Since patient primary cells can be very difficult to access in particular in very young children or in patients who have undergone stem cell transplantation, we differentiate macrophages from induces pluripotent stem cells. We use CRISPR/Cas9 to produce cells with defined genetic defects. This project will provide a unique insight into translational research from patient genetics towards immunology mechanisms and will allow the graduate student to interact with both basic researchers and clinicians.