Almost all people with ulcerative colitis (UC) make antibodies against a protein dimer called integrin _v_6 on intestinal epithelial cells (IECs) lining the colon. People without UC do not. These “autoantibodies” often occur a decade before UC diagnosis, suggesting they may play a causal role very early in UC onset. Indeed, _v_6 is known to activate one of the most important natural immunosuppressants in the colon, called TGF-_, through a mechanism involving the exact part of _v_6 that these autoantibodies block. We have found that UC patients do not release as much TGF-_ from their colon lining nor have as much TGF-_ in their blood as people without UC. We have also shown that mice lacking _v_6 specifically in their IECs are predisposed to get colitis and show defects resembling UC in both their IECs and intestinal immune cells.
Using these modified mice plus cultures of human colon IECs and immune cells with anti-_v_6 autoantibodies from UC patients, we propose to determine how _v_6 loss or blockade alters IEC characteristics, including their barrier function, to cause a leaky gut. We will also study how an _v_6 defect makes immune cells more prone to cause inflammation and thus UC.
