Characterizing Antigen Presentation and Adaptive Immunity in Inflammatory Bowel Disease

About This Grant

Project Summary/Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory process initiated in the intestinal mucosa, typically onset in young adults. IBD causes severe morbidity and emergent complications often necessitating surgery, with a high proportion of IBD patients relapsing or being unresponsive to anti-TNF therapy. Despite the urgent clinical need for improved IBD treatments, pathophysiology of IBD remains incompletely understood, thought to result from complex genetic and environmental factors. Abnormalities in adaptive and innate immunity, cellular and ER stress, increased mucosal barrier permeability, dysbiosis, and genetic variants in autophagy and immune signaling components may contribute to increasingly pro-inflammatory gut immune dynamics, ultimately spreading to extra-intestinal manifestations in almost half of patients. Adaptive immunity, especially the Th17 T-cell subset converting to a pro-inflammatory phenotype, has been widely accepted as an important proponent of inflammation in IBD, with specific microbial strains and viral integration implicated as possible drivers. However, the antigen presentation landscape of T-cell epitopes has never been systematically characterized. In this research effort, we will profile antigen presentation by experimental immunopeptidomics, then computationally prioritize these HLA-presented peptides for immunogenicity, also examining molecular mimicry with self-antigens, to more deeply understand IBD pathophysiology (Aim 1). Adaptive immune responses can be triggered by ER stress, a biochemically complex phenomenon whose far-reaching role in IBD contributes to numerous pathologic features. Since evidence shows ER stress alters antigen presentation, we will attempt to draw a mechanistic link in the context of IBD, resolving specific antigen presentation changes induced by ER stress (Aim 2). Finally, we will attempt to validate immunogenicity of peptide epitopes by detecting antigen-specific T-cell receptors. Combining the abundant IBD resources in our biobanks and IBD Center with the expertise of an experienced, interdisciplinary team, we will endeavor to answer these important questions about adaptive immunity in IBD, while creating a high-quality dataset that lays the groundwork for future studies.