A Keio University-led study linked intestinal epithelial cell signaling to the initiation of neuroinflammation in multiple sclerosis models. Researchers reported in Science Immunology that intestinal epithelial cells promote TH17 differentiation and the migration of encephalitogenic CD4+ T cells, with the mechanism tied to MHC class II expression on IECs. The study analyzed intestinal tissue from patients with multiple sclerosis and compared it with experimental autoimmune encephalomyelitis mouse models. It found increased TH17 cells and upregulated MHC II on IECs in both settings, and demonstrated that deleting MHC II in IECs reduced gut TH17 accumulation and lowered EAE severity. The work points to intestinal immunity as a therapeutic site, including the potential for strategies that modulate IEC antigen presentation rather than focusing only on B-cell targets used in existing MS therapies.