Mucosal B Cell Expansion and Maturation Contribute to Colitis Pathogenesis.

Abstract

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing and remitting mucosal inflammation of the colon. While active UC mucosa is characterized by dysregulated B cell responses and increased B cell and IgG plasma cell populations, targeting CD20-expressing B cells in UC has proven ineffective. METHODS: We conducted an exploratory single-cell transcriptomic analysis of colonic biopsies obtained from UC patients with (n = 5) or without (n = 5) active inflammation, and non-UC controls (n = 4). To explore whether B cells contribute to colitis severity, we transferred various ratios of spleen-derived naive B cells with CD45RBhigh T cells into severe combined immune deficient mice to induce colitis. RESULTS: Our analysis identified a distinct subset of naive (MS4A1+CD27-IGHD+TCL1A+) B cells that are significantly enriched and present a more matured phenotype in inflamed compared to non-inflamed biopsies from UC patients. Cell-cell communication analysis indicated that naive B cells interacted predominantly with CD4+ T cell subsets. In the mice transfer colitis model, co-transfer of naive B cells at a ratio of 1-2 T and B cells, respectively, showed an increased maturation and activity, which led to exacerbation of colitis as measured by weight loss, increased colon density, and histological inflammation. CONCLUSION: Our findings suggest that naive B cells expand in actively inflamed mucosa from UC patients and play a pathogenic role in experimental colitis.