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Autoantibodies against the epithelial-restricted integrin \u03b1v\u03b26 are a highly specific biomarker of UC that can precede clinical diagnosis by up to 10 years. Because \u03b1v\u03b26 activates TGF\u03b2 at epithelial surfaces, we hypothesized that UC-associated \u03b1v\u03b26 autoantibodies inhibit mucosal TGF\u03b2 activation and disrupt epithelial homeostasis. We showed that \u03b1v\u03b26 autoantibodies were enriched in UC and that IgG from autoantibody-positive individuals inhibited \u03b1v\u03b26\u2013dependent activation of TGF\u03b2. \u03b1v\u03b26 blockade dampened TGF\u03b2 signaling and altered differentiation\u2013associated gene programs in human intestinal epithelial cells. In mice, deletion of \u03b1v caused expansion of inflammation-associated goblet cells in the colon and changes in intestinal immune cells. Using a novel mouse model, we showed that \u03b1v\u03b26-specific autoantibody disrupted epithelial\u2013immune crosstalk and increased susceptibility to DSS colitis. Together, these findings establish anti-\u03b1v\u03b26 autoantibodies as active inhibitors of epithelial TGF\u03b2 signaling, constituting a\n                  <jats:italic>de facto<\/jats:italic>\n                  anti-cytokine response, rather than passive biomarkers. By linking preclinical seropositivity to impaired epithelial signaling and heightened susceptibility to colitis, this work identifies epithelial \u03b1v\u03b26\u2013dependent TGF\u03b2 activation as a pathway that may be leveraged to modify disease risk or limit disease severity.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>UC-associated autoantibodies impair epithelial TGF\u03b2 activation, alter mucosal homeostasis, and predispose to colitis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.12.709585","type":"posted-content","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T04:00:23Z","timestamp":1773633623000},"source":"Crossref","is-referenced-by-count":1,"title":["UC-associated autoantibodies to \u03b1v\u03b26 inhibit mucosal TGF\u03b2 activation and predispose to intestinal inflammation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5802-8140","authenticated-orcid":false,"given":"Kayla J.","family":"Fasano","sequence":"first","affiliation":[{"name":"Benaroya Research Institute, Seattle, WA, United States"},{"name":"Department of Immunology, University of Washington, Seattle, WA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3717-1992","authenticated-orcid":false,"given":"Anna E.","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute, Seattle, WA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8170-2474","authenticated-orcid":false,"given":"Jane F.","family":"Madden","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute, Seattle, WA, United 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