Systems medicine approach towards the immune repertoire in inflammatory bowel diseases (IBD)

• Applicant: Professor Dr. Andre Franke
• Subject Area: Gastroenterology ; Human Genetics
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409661003

Inflammatory bowel diseases (IBD) are chronic-remittent inflammatory diseases of the gastrointestinal tract. IBD aetiology is hypothesized to be influenced by a number of genetic, immunological and environmental factors. However, IBD is still poorly understood and the search of the exact disease causes is ongoing. Inflammation initiation and progression are thought to be T cell mediated in IBD and are therefore dependent on the interaction between the T-cell receptor (TCR) and the antigen-human leukocyte antigen (HLA) complex. Recent observations, such as the dramatic expansion of IgG+ plasma cells in the inflamed lamina propria of IBD patients, have brought attention to the role of B cells and their B cell receptors (BCRs) in IBD. While the origin of the antigen(s) triggering the abnormal immune response in IBD remains to be elucidated, increasing evidence is pointing towards the intestinal microbiota.Here, we propose to employ a unique sample collection setup for a comprehensive targeted sequencing approach to gain insights into the BCR-TCR-antigen-HLA facets of IBD. To the applicants' knowledge, this comprehensive multi-dimensional approach has never before been applied in IBD research. In collaboration with the Surgical Department of the University Hospital Schleswig-Holstein (UKSH), we started collecting inflamed and non-inflamed gut tissue, together with mesenteric lymph nodes (MLN) and peripheral blood mononuclear cells (PBMCs) from IBD patients undergoing bowel resection. We will perform HLA typing, combined with TCR and BCR repertoire (the collection of the different BCR/TCR sequences of an individual) profiling of sorted cell subpopulations and, most interestingly, of antigen reactive T cells of the gut, and finally analysis of the patients' gut microbiome. The strength of our approach is an intra-individual comparison of multiple tissues. Strong inter-individual variability of the immune repertoire and HLA locus reduce the power of stratified inter-individual comparisons. Therefore, our intra-individual analyses will result in a group of disease-relevant candidate TCR/BCR/microbiome species, reducing complexity on the intra-individual-level before we next search for recurrent patterns between patients.In particular, we will compare the BCR/TCR repertoire and the microbial composition of inflamed and non-inflamed gut tissue, thus aiming at the identification of disease-specific bacterial signatures and B/T cell clones, hereafter referred to as clonotypes. For the same purpose, the immune repertoire of MLN, putative location of T cell activation and somatic hypermutation for B cells, will also be analysed. Finally, immune repertoire analysis of PBMCs will serve to identify normal circulating clonotypes. Thus, we will acquire a unique and comprehensive picture of the intestinal and circulating repertoire of adaptive immune cells in IBD patients, in relation to their HLA status and microbial composition at the site of inflammation.

• DFG Programme: Research Grants
• International Connection: Russia
• Partner Organisation: Russian Foundation for Basic Research
• Cooperation Partner: Ilgar Mamedov, Ph.D.