Tu129 - Deep Phenotyping Identifies Inflammatory Clonal B Cell Expansions in IBD

Will Rae – Cambridge University; Laura Bergamaschi – Cambridge University; Diana Pombal – Cambridge University; Nurulamin Noor – Cambridge University; Lukas Unger – Medical University of Vienna; Giulia Manferrari – Cambridge University; Sofie Tolmeijer – Cambridge Unviersity; Samuel Rubin – Stanford University; Raoul Sojwal – Stanford University; Brandon Lam – Stanford University; Rachael Bashford-Rogers – Cambridge University; Anton Stift – Medical University of Vienna; Stephan Rogalla – Stanford University; John Gubatan – Stanford University; James Lee – Francis Crick Institute; Kenneth Smith – Cambridge University; Scott Boyd – Stanford University; Eoin McKinney – Cambridge University; Paul Lyons – Cambridge University

Abstract Text: B cells play an important role in gut homeostasis. Dysregulated B cell populations have been reported in patients with inflammatory bowel disease (IBD), but how these B cell perturbations contribute to disease remains largely unknown. We studied the B cell immunophenotype, serological profile, transcriptome, and B cell receptor (BCR) repertoire from patients with active IBD. This multi-omic approach identified several alterations in IBD suggesting host-microbiome influences and a pathogenic role of B cells.

Increased antibodies against Klebsiella Pneumonia, Lactobacillus species, and Enterococcus faecalis indicated microbiome dysregulation. An inflamed phenotype was evident with up-regulation of interferon and NOD-like receptors signalling pathways.

The BCR repertoire in blood and mesenteric lymph nodes draining inflamed regions of bowel showed a global reduction in somatic hypermutation compared to healthy controls, despite the presence of well formed germinal centres. Shared BCR clones were uniquely present between patients with Crohn’s disease (CD), but not in healthy controls nor in patients with Ulcerative colitis. These shared clones were present in both lymph nodes and circulating plasmablasts, suggesting a specific CD-associated antigen pattern driving inflammatory B cell responses.

These results further elucidate the dysregulation of B cells in IBD. The identification of shared B cell clones across patients with CD sheds further light on the pathogenesis CD and the interaction with the microbiome. These findings warrant further work to potentially help in the diagnosis of disease endotypes and for possible novel treatment strategies.