Understanding the role of B cells in the pathogenesis of Inflammatory Bowel Disease

Abstract

Inflammatory Bowel Disease (IBD) is a chronic relapsing-remitting disease comprising of two broad phenotypes: Ulcerative Colitis (UC) and Crohn's Disease (CD). The worldwide prevalence and incidence of IBD is on the rise and understanding the disease pathogenesis is crucial to address current gaps in management and the development of new approaches to diagnose and treat IBD. Recent advances in single cell and high-resolution technologies, including RNA-seq and spatial transcriptomics (ST), are allowing for increasingly detailed interrogation into the disease process. Here we have developed a high-resolution analytical pipeline to analyze existing scRNA-seq datasets to identify novel immune cell subsets across IBD states. We have discovered that human intestinal tissue contains unique IgG plasma B cells bearing IGKV1-12 light chain genes that may be pathogenic in CD and UC. In contrast, healthy control tissue contains numerous IgA plasma cells which occupy superficial layers of the mucosa and mediate a controlled response to insults. BLAST analysis of the sequence of this cell cluster revealed close similarity to pathogenic genomes of Coxsackie, an enterovirus previously associated with intestinal inflammation and cross reactivity. To better understand the role of these immune cells in IBD pathogenesis, new ST datasets were created using the 10X Visium platform. This allowed us to confirm the presence of these plasma cells in human ileum and segment their anatomical location - as well as the cells they interact with - in inflamed vs uninflamed CD-affected tissue. Together, these results provide compelling evidence for a role of B cells - particularly distinct plasma cells - in IBD pathogenesis. The data suggests there are strong links between environmental triggers, especially viruses, class-switched B cells and intestinal inflammation. This work lays the foundation for future functional studies as well as the development of new diagnostics and treatments for IBD.