The loss of SHP2 enhances gut germinal center function to alleviate intestinal inflammation 9076

Abstract Description The germinal center (GC) is crucial for generating high-affinity antibodies and memory B cells, essential for long-term immunity and gut homeostasis. In ulcerative colitis (UC), the impact of local inflammation on GC dynamics and their therapeutic potential remains unclear. This study aims to clarify these mechanisms and identify treatment strategies. The analysis examined the link between tissue pathology and colitis progression, as well as B cell scRNA-seq data from UC patients. Additionally, DSS-induced colitis was modeled in mice, with conditional SHP2 knockouts were generated using CD19-Cre mice. Techniques including MS-based proteomics and flow cytometry were utilized to assess target levels and B cell signatures. Initially, it was observed that the number of gut GC inversely correlated with colitis severity. DSS-induced colitis reduced gut localized GC size and AID expression, but not in spleen. ScRNA-seq and IHC data indicated that phosphatase SHP2 affects GC malformation. Proteomic analysis further revealed down-regulated IGHM post-immunization in SHP2-deficient B cells. In vivo, colitis symptoms were mitigated, IL-6 levels decreased, and colonic morphology improved. Besides, there was also an increase in GC B cells while a decrease in luminal IgM, suggesting enhanced maturation. These results underscore the importance of gut-associated GC in colitis. Modulating GC activity via SHP2 inhibition may offer a promising strategy to mitigate gut inflammation. Topic Categories Mucosal and Regional Immunology (MUC)