Journal Article

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

Lord, James D, Harrison, Oliver J, Madden, Jane F, Fasano, Kayla J, Shows, Donna M, Edwards, Thomas H, Stefani, Caroline, Kugler, David G, Speake, Cate, Scheiding, Sheila, Tung, Lin Wei, Mauk, Kelsey E, Smithmyer, Megan E, Yoshida, Anna E, Lacy-Hulbert, Adam, Manjunath, Adarsh B

2026

Overview

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 αvβ6 are a highly specific biomarker of UC that can precede clinical diagnosis by up to 10 years. Because αvβ6 activates TGFβ at epithelial surfaces, we hypothesized that UC-associated αvβ6 autoantibodies inhibit mucosal TGFβ activation and disrupt epithelial homeostasis. We showed that αvβ6 autoantibodies were enriched in UC and that IgG from autoantibody-positive individuals inhibited αvβ6-dependent activation of TGFβ. αvβ6 blockade dampened TGFβ signaling and altered differentiation-associated gene programs in human intestinal epithelial cells. In mice, deletion of αv caused expansion of inflammation-associated goblet cells in the colon and changes in intestinal immune cells. Using a novel mouse model, we showed that αvβ6-specific autoantibody disrupted epithelial-immune crosstalk and increased susceptibility to DSS colitis. Together, these findings establish anti-αvβ6 autoantibodies as active inhibitors of epithelial TGFβ signaling, constituting a anti-cytokine response, rather than passive biomarkers. By linking preclinical seropositivity to impaired epithelial signaling and heightened susceptibility to colitis, this work identifies epithelial αvβ6-dependent TGFβ activation as a pathway that may be leveraged to modify disease risk or limit disease severity.

• Publisher: Cold Spring Harbor Laboratory Preprints