Center Director Benaroya Research Institute Seattle, Washington, United States
Disclosure(s):
Adam Lacy-Hulbert, PhD: No financial relationships to disclose
Introduction/Rationale: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by inflammation of the colonic mucosa. Recent reports have shown that UC patients develop autoantibodies against the epithelial cell-specific integrin αvβ6 that can be detected up to 10 years prior to clinical diagnosis. A key function of αvβ6 is activation of the cytokine TGFβ, a central regulator of gut immunity and homeostasis. We hypothesized that autoantibodies may predispose individuals to chronic intestinal inflammation by disrupting αvβ6 activation of TGFβ.
Methods: Serum and mucosal biopsies from UC patients and matched healthy controls were analyzed for anti-integrin autoantibodies by ELISA, and numbers of autoantibody-producing cells by ELISPOT. The ability of autoantibodies to block TGFβ activation was assessed using patient samples. Effects of αvβ6 blockade on intestinal epithelial cell function were tested using colonic cell lines and primary human epithelial cells.
Results: We detected αvβ6 autoantibodies in almost all UC patients tested, confirming earlier reports. We identified αvβ6-specific B cells and autoantibodies in colonic biopsies from UC patients, demonstrating that antibodies are produced at sites of inflammation in UC. We found that IgG from autoantibody-positive UC patients inhibited αvβ6-mediated TGFβ activation and that αvβ6 blockade in human intestinal epithelial cells (IECs) decreased TGFβ-response genes while upregulating goblet cell-associated genes. In a mouse model in vivo, loss of epithelial αvβ6 caused goblet cell expansion in the colon and increased susceptibility to DSS-induced colitis.
Conclusion: Collectively, our data support a model in which UC-associated αvβ6 autoantibodies disrupt TGFβ signaling in IECs, predisposing individuals to colitis. These findings suggest that αvβ6 autoantibodies serve not only as an early biomarker but also contribute to development of disease and may represent a novel therapeutic target.
