Disruption of Integrin ?vß6 in Intestinal Epithelial Cells Predisposes to Ulcerative Colitis 4493

Description The underlying mechanisms that lead to the development of ulcerative colitis (UC) are poorly understood. Recently it has been reported that almost all patients with UC have autoantibodies to the integrin ?vß6 which are not seen in other forms of IBD. Furthermore, anti-?vß6 antibodies can precede clinical diagnosis of UC by up to 10 years and were associated with increased adverse outcomes, suggesting they may represent a critical prerequisite for development of disease. A major function of ?vß6 is the activation of the cytokine TGF-ß, a key regulator of intestinal barrier function. We have found that UC patients have decreased serum TGF- ß1 levels and UC intestinal biopsies produce less TGF- ß1 than healthy controls. We have also shown that autoantibodies from UC patients can inhibit ?vß6 function. To further investigate the role of ?vß6 in intestinal inflammation, we generated mice lacking ?v integrins in the intestinal epithelium. These mice exhibit more severe intestinal inflammation and mortality in the DSS colitis model than littermate controls. We find that colonic epithelial cells in these mice have gene expression changes consistent with increased antimicrobial responses and barrier disruption, including gene sets that are altered in intestinal epithelial cells from UC patients. Taken together, we hypothesize that intestinal ?vß6 activates TGF-ß to promote immune homeostasis, and that disruption of ?vß6 function in healthy individuals induces a pre-colitis state. Funding Sources NIDDK R01 DK136071; Rainin Foundation Topic Categories Mucosal and Regional Immunology (MUC)