Background and current state of research
For Crohn’s disease (CD) and ulcerative colitis (UC), the main entities of inflammatory bowel disease (IBD), our recent genetic association analyses have identified more than 200 risk loci [1-2]. Especially a strong evidence of association to the major histocompatibility complex (MHC) has been identified and therefore a high-density mapping of MHC was recently performed to identify causal candidate alleles [3].
To this end, only a fraction of the disease etiology can be attributed to genetic susceptibility and major environmental factors and triggers of the disease remain to be identified [4]. IBD may be an autoimmune disease or a dysregulated immune response against environmental antigens such as certain gut bacteria of a dysbiosed microbiota [5-6].
Our goals
On the basis of the knowledge of different risk factors for IBD we aim to find out if there are candidate antigens that are responsible to induce the inflammation. We will base our research on state-of-the-art fine mapping data for the major histocompatibility complex. The comprehension of the exact immunogenetics and the disturbed immunology might lead to the development of potential vaccines or to environmental risk factors that can be changed.
How to get there
We aim to identify epitopes that bind specifically to the risk alleles or the protective alleles. To deal with the huge number of known epitopes we will use sophisticated computational approaches for reducing the number of candidate peptides.
In this subproject we will collaborate with the Bioinformatics Group of Prof. Shoba Ranganathan at the Macquarie University Sydney, which is specialized among others in structural biology.
More information
[1] Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nature genetics 42, 1118-25 (2010).
[2] Jostins et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–24 (2012).
[3] Goyette, P. et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nature Genetics 47, 172-179 (2015).
[4] Ellinghaus, D. et al. The genetics of Crohn’s disease and ulcerative colitis – status quo and beyond. Scandinavian Journal of Gastroenterology 50, 13-23 (2015).
[5] Sollid, L. & Jabri, B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nature reviews. Immunology 13, 294-302 (2013).
[6] Wu H. et al. Gut-Residing Segmented Filamentous Bacteria Drive Autoimmune Arthritis via T Helper 17 Cells. Immunity 32, 815-827 (2010).