In immune-mediated diseases such as type1 diabetes, target-cell autoantibodies have emerged as important clinical biomarkers of pre-clinical disease progression and mechanistic disease subsets. However, with the focus on genetics, inflammatory effectors, and microbiome, there has not been a modern search for such antibody biomarkers and the potential contribution of anti-epithelial autoimmunity in IBD. This project tests the hypothesis that ulcerative colitis phenotypes are distinguished by autoantibodies to mucosal epithelial proteins, addressed in two aims. In the first aim, we apply the innovative peptide expression display (PED) technology to display and analyze the antigenic epithelial peptidome. This includes bioinformatically determining a comprehensive tabulation of human proteins with high likelihood for antigenicity and ileal-colonic epithelial expression; and, representing these proteins as tiled peptide epitopes with linked cognate oligonucleotides suitable for NGS-based identification and quantitation. In the second aim, we will assess archival sera of 654 well-characterized colonic IBD patients and non-IBD controls to quantitate individual profiles of epithelial protein binding in relation to two outcomes of ulcerative colitis (UC). The significance of the project has been endorsed by the IBD Genetics Consortium (IBDGC), which made the UC colectomy cohort a research priority, and will collaborate with this R21 via archival serum samples and associated genetics and clinical metadata from the consortium UC patients and controls. Our primary study will compare 300 UC subjects, equally divided into severe and mild phenotypes of outcome based on time to colectomy. Our secondary study will compare 154 UC post-colectomy pouch patients, divided into severe and absent pouchitis phenotypes. We will also study two age-matched reference populations. Bioinformatic analyses will test for shared peptide specificities associated with disease state (UC vs. non-IBD controls) and each of the two extreme phenotypes (severe vs. mild UC; chronic pouchitis vs. late non-pouchitis). We also will perform exploratory tests for the role of IBD predictive risk scores and select genetic loci on autoantibody specificities. If successful, this project will establish feasibility for the hypothesis, and foundational targets to pursue mechanistic and clinical biomarker studies that may validate and refine its implications for IBD pathogenesis and clinical applications.
In immune-mediated diseases such as type-1 diabetes, target-cell autoantibodies have emerged as important clinical biomarkers of pre-clinical disease progression and mechanistic disease subsets. Here we propose the first modern search for autoantibody biomarkers in ulcerative colitis, and a test of the hypothesis that anti-epithelial autoimmunity is a contributor to extreme phenotypes in this disease. If successful, this project will establish feasibility for the hypothesis, and foundational targets to pursue mechanistic and clinical biomarker studies that may validate and refine its implications for IBD pathogenesis and clinical applications.
