P092 Pathogenic B-cell response in ulcerative colitis that associates with treatment resistance and disease complications
M. Uzzan1, J. Martin2, E. Keningsberg2, T. Castro-Dopico3, R. Huang4, R. Ungaro1, B. Cohen1, A. Rahman5, A. Rosenstein1, S. Gurunathan1, M. Dubinsky1, M. Clatworthy3, M. Suarez-Farinas6, C. Argmann6, J.F. Colombel1, S. Mehandru7
1Icahn School of Medicine at Mount Sinai, Gastroenterology, New York, USA, 2Icahn School of Medicine at Mount Sinai, Precision Immunology Institute, New York, USA, 3University of Cambridge, Medicine, Cambridge, UK, 4Icahn School of Medicine at Mount Sinai, Population Health Science and Policy, New york, USA, 5Icahn School of Medicine at Mount Sinai, Human Immune Monitoring Center, New York, USA, 6Icahn School of Medicine at Mount Sinai, Genetics and Genomics, New York, USA, 7Icahn School of Medicine at Mount Sinai, Department of Medicine Gastroenterology, New York City, USA
Background
Among the adaptive immune cells, B cells, dominated by IgA producing plasma cells (PC), are critical for intestinal homeostasis. However, the B-cell response remains under studied in ulcerative colitis (UC).
Methods
Using single-cell RNA sequencing (scRNA seq), single-cell IgH sequencing (sc IgH seq), multiparameter flow cytometry (FC), mass cytometry (MC) and immunofluorescent microscopy (IF), we have comprehensively defined the landscape of intestinal and circulating B cells in patients with UC. A Cohort of 88 patients with active UC, 14 patients with quiescent UC and 43 healthy volunteers were recruited. Two validation cohorts comprising of 53 patients with active UC, 59 patients with quiescent UC and 65 healthy volunteers (Validation cohort 1) and 65 patients with active UC, 42 patients with quiescent UC and 36 healthy volunteers (Validation cohort 2) were also studied.
Results
scRNA seq and FC demonstrate a dramatic increase in proliferating (Ki67+) plasmablasts (PB) as well as IgG+ PC in the inflamed colon of UC patients. Additionally, a significant increase in short-lived (CD19+CD45+) PC was observed during colonic inflammation. scIgH seq further demonstrates a significant decrease in somatic hypermutations and the diversity of intestinal PC of patients with active UC. Genes associated with Fc-dependent macrophage signalling were enriched in areas of active disease and were associated with non-response to TNF therapy. In circulation, a significant increase in a4b7+ gut-homing PC was noted that related to disease extent, severity and complications (defined by treatment non-response, hospitalisations and surgery).
Conclusion
Active UC results in an immature, IgG-dominated PB/PC response in inflamed GI tissue and an increase in the frequency of gut-homing PC in circulation that relates to disease activity and complications and may be used to monitor disease course. These data provide novel insights into the pathogenesis of UC with major implications for existing and emerging therapeutic agents.