UC-associated autoantibodies to αvβ6 inhibit mucosal TGFβ activation and predispose to intestinal inflammation

Lacy-Hulbert, A.; Fasano, K. J.; Yoshida, A. E.; Madden, J. F.; Mauk, K. E.; Tung, L. W.; Edwards, T. H.; Shows, D. M.; Stefani, C.; Kugler, D.; Scheiding, S.; Manjunath, A. B.; Smithmyer, M. E.; Harrison, O. J.; Speake, C.; Lord, J. D.

doi:10.64898/2026.03.12.709585

bioRxiv · 10.64898/2026.03.12.709585

UC-associated autoantibodies to αvβ6 inhibit mucosal TGFβ activation and predispose to intestinal inflammation

Lacy-Hulbert, A.·Fasano, K. J.·Yoshida, A. E.·Madden, J. F.·Mauk, K. E.·Tung, L. W.·Edwards, T. H.·Shows, D. M.·Stefani, C.·Kugler, D.·Scheiding, S.·Manjunath, A. B.·Smithmyer, M. E.·Harrison, O. J.·Speake, C.·Lord, J. D.

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Abstract

Ulcerative colitis (UC) is characterized by epithelial barrier dysfunction and dysregulated mucosal immune responses; however, the mechanisms driving disease onset remain poorly defined. Autoantibodies against the epithelial-restricted integrin v{beta}6 are a highly specific biomarker of UC that can precede clinical diagnosis by up to 10 years. Because v{beta}6 activates TGF{beta} at epithelial surfaces, we hypothesized that UC-associated v{beta}6 autoantibodies inhibit mucosal TGF{beta} activation and disrupt epithelial homeostasis. We showed that v{beta}6 autoantibodies were enriched in UC and that IgG from autoantibody-positive individuals inhibited v{beta}6-dependent activation of TGF{beta}. v{beta}6 blockade dampened TGF{beta} signaling and altered differentiation-associated gene programs in human intestinal epithelial cells. In mice, deletion of v caused expansion of inflammation-associated goblet cells in the colon and changes in intestinal immune cells. Using a novel mouse model, we showed that v{beta}6-specific autoantibody disrupted epithelial-immune crosstalk and increased susceptibility to DSS colitis. Together, these findings establish anti-v{beta}6 autoantibodies as active inhibitors of epithelial TGF{beta} signaling, constituting a de facto anti-cytokine response, rather than passive biomarkers. By linking preclinical seropositivity to impaired epithelial signaling and heightened susceptibility to colitis, this work identifies epithelial v{beta}6-dependent TGF{beta} activation as a pathway that may be leveraged to modify disease risk or limit disease severity. One Sentence SummaryUC-associated autoantibodies impair epithelial TGF{beta} activation, alter mucosal homeostasis, and predispose to colitis.

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Lacy-Hulbert, A., Fasano, K. J., Yoshida, A. E., Madden, J. F., Mauk, K. E., Tung, L. W., Edwards, T. H., Shows, D. M., Stefani, C., Kugler, D., Scheiding, S., Manjunath, A. B., Smithmyer, M. E., Harrison, O. J., Speake, C., Lord, J. D.. 2026-03-15. UC-associated autoantibodies to αvβ6 inhibit mucosal TGFβ activation and predispose to intestinal inflammation. https://doi.org/10.64898/2026.03.12.709585

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