Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance

Crohn's disease (CD) is a condition characterized by excessive numbers of a ctivated T cells in the mucosa, We investigated whether a defect in apoptos is could prolong T cell survival and contribute to their accumulation in th e mucosa, Apoptotic, Bcl-2(+), and Bax(+) cells in tissue sections were det ected by the TUNEL method and immunohistochemistry. T cell apoptosis was in duced by IL-2 deprivation, Fas Ag ligation, and exposure to TNF-alpha and n itric oxide. TUNEL+ leukocytes were few in control, CD, and ulcerative coli tis (UC) mucosa, with occasional CD68(+) and myeloperoxidase(+), but no CD4 5RO(+), apoptotic cells. Compared with control and UC, CD T cells grew rema rkably more in response to IL-2 and were significantly more resistant to IL -2 deprivation-induced apoptosis, CD T cells were also more resistant to Fa s- and nitric oxide-mediated apoptosis, whereas TNF-alpha failed to induce cell death in all groups. Compared with control, CD mucosa contained simila r numbers of Bcl-2(+), but fewer Bax(+), cells, while UC mucosa contained f ewer Bcl-2(+), but more Bax(+), cells. Hence, the Bcl-2/Bax ratio was signi ficantly higher in CD and lower in UC, These results indicate that CD may r epresent a disorder where the rate of T cell proliferation exceeds that of cell death. Insufficient T cell apoptosis may interfere with clonal deletio n and maintenance of tolerance, and result in inappropriate T cell accumula tion contributing to chronic inflammation.