Functional genomics of pediatric inflammatory bowel diseases

Inflammatory bowel diseases (IBDs) comprise a heterogeneous group of disorders, classified as Crohn`s disease, ulcerative colitis, and indeterminate colitis. The molecular etiologies of inflammatory bowel diseases are incompletely understood. Studies in transgenic murine model systems and genome wide SNP-based association studies have provided preliminary insights into the genetic complexity underlying these inflammatory conditions. However, the results of these studies remain mostly associative and cannot provide mechanistic proof. Studying monogenic diseases, such as autosomal recessive IBD, provides an alternative approach to identify genes causing inflammatory bowel disease. In this project, we will use state-of-the art genomic technologies including high-resolution SNP arrays and next generation sequencing to elucidate hitherto unknown genetic defects in pediatric IBD patients. We will systematically assess the functional impact of the genetic deficiencies using a spectrum of biochemical, immunological and cellular imaging technologies. We expect that our investigations will lay the foundation for more specific or targeted therapies in defined subgroups of pediatric IBD patients in the future.

Inflammatory bowel diseases (IBDs) comprise a heterogeneous group of disorder which are classified as Crohns disease, ulcerative colitis and indeterminate colitis. Despite their increasing frequency in the developed world, underlying mechanisms are only incompletely understood. SNP-based genome wide association studies have provided some insights into potential disease causing mechanisms, however, most of these studies lack mechanistic proof. In this project we investigated patients with neonatal and infantile IBD, which presented disease manifestations before the age of 2 years. In our genetic analysis, we could identify patients with novel mutations in the recently published genes IL21R (Erman B et al. Haematologica 2015), TTC7A (Woutsas S et al. Blood 2015) and LRBA (Seidel MG et al. J Allergy Clin Immunol 2015; Serwas NK et al. Inflamm Bowel Dis 2015). Furthermore, we could identify IL-21 deficiency as a novel, previously unrecognized cause for infantile IBD with combined variable immunodeficiency. Our work suggests that this form of IBD can be treated with recombinant IL-21 as the cellular phenotype of reduced class-switched B cells was reverted by addition of this protein (Salzer E et al. J Allergy Clin Immunol 2014). Furthermore, we could identify a novel deficiency caused by mutation in a gene encoding a guanine nucleotide exchange factor (GEF) and associated with bowel inflammation. We provide evidence that this GEF regulates the trafficking of CTLA-4 through an interaction with the small GTPase RAB11 which is abrogated in the mutated setting. Strikingly, the patients phenotype was revertible by CTLA-4-Ig therapy. In summary, we uncovered two novel monogenic diseases which provided useful mechanistic insights in the disease etiologies of IBD. Furthermore, their discovery suggested potential treatment options for the affected patients. This important project was only possible through the funding by the FWF and we gratefully acknowledge the support we received through the FWF grant P24999-B30 for the above-mentioned scientific project.