○Makoto Kodama1 Yoshihiro Nagase1 Shu Kato1 Asuka Furukawa1Kurara Yamamoto1 Kouhei Yamamoto11 Dept. of Pathol, Inst. of Sci. Tokyo.PurposeTertiary lymphoid structures (TLS) are ectopic lymphoid aggregates commonly observed in chronic inflammatory diseases, including inflammatory bowel disease. While traditionally seen as secondary responses to ongoing inflammation, we hypothesized that TLS are central to the pathology of chronic inflammation and may actively contribute to lesion formation. This study aimed to investigate the role of TLS in inflammatory bowel diseases, and to clarify their association with disease pathology.MethodsBiopsy and surgical samples from patients with ulcerative colitis and Crohn’s disease were analyzed using spatial profiling techniques, including Xenium and PhenoCycler. In addition, public single-cell and bulk RNA sequencing datasets were used for gene set enrichment analysis, focusing on oxidative phosphorylation and TLS-related gene signatures.ResultIn inflamed intestinal mucosa, plasma cells that produce IgG and originate from TLS displayed increased oxygen consumption, which was associated with local mucosal ischemia. The presence of TLS was also linked to elevated levels of C-reactive protein and the formation of deeper ulcers. Regarding treatment, cells expressing TNFα were primarily located within TLS, and the administration of TNFα inhibitors led to a reduction in these cells, as well as follicular dendritic cells and the overall structure of TLS. Notably, the pre-treatment status of TLS was a predictor of the response to anti-TNF therapy.DiscussionTLS appear to contribute directly to ulcer formation in IBD, rather than being mere byproducts of inflammation. Similar roles may exist in diseases like rheumatoid arthritis and psoriasis. Assessing TLS could help predict treatment response and support personalized therapy. Ongoing work aims to develop TLS-targeted treatments for chronic inflammatory conditions.Tertiary lymphoid structures as a central player in inflammatory bowel disease 46P 016
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