B cells in the mesenteric fat contribute to Crohn’s disease

Abstract

Abstract Crohn’s disease [CD] is one of the two common forms of inflammatory bowel disease and it affects over half a million Americans. Like many other diseases marked by chronic inflammation, some patients with CD develop tertiary lymphoid organs [TLO] in regions of the gut with active disease. TLOs are organized clusters of adaptive immune cells, similar in function and structure to secondary lymphoid organs. Recently, we found B cell rich lymphoid aggregates in the mesenteric fat of CD patients positioned along dramatically remodeled lymphatic vessels, but their function, specifically of the B cells within these aggregates, is completely unknown. Using complementary imaging, flow cytometry, and single cell RNA sequencing approaches, we analyzed B cells present in the mesenteric fat from CD patients. Whereas B cells were essentially not present in the mesentery under homeostatic conditions, they were significantly increased in the inflamed mesenteric fat of CD patients. Single cell RNA sequencing data revealed differences in B cell populations in the mesenteric fat that potentially implicate B cells as contributing to lymphangiogenesis associated with TLOs. Simultaneously, we used a murine model of ileal inflammation to probe mechanism. Imaging and flow cytometry showed that the B cells in TLOs from TNFΔARE/+mice were comparable to the B cells from CD patients. Additionally, TNFΔARE/+/μMT mice, which lack B cells, further revealed that B cells may be required for the lymphatic remodeling seen in the mesentery.