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

Kenji Ina, Jugoh Itoh, Kohei Fukushima, Kazuo Kusugami, Takeo Yamaguchi, Kazuhiro Kyokane, Akira Imada, David G. Binion, Alessandro Musso, Gail A. West, George M. Dobrea, Thomas S. McCormick, Eduardo G. Lapetina, Alan D. Levine, Clifford A. Ottaway, Claudio Fiocchi

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300 Citations (Scopus)

Abstract

Crohn's disease (CD) is a condition characterized by excessive numbers of activated T cells in the mucosa. We investigated whether a defect in apoptosis could prolong T cell survival and contribute to their accumulation in the mucosa. Apoptotic, Bcl-2+, and Bax+ cells in tissue sections were detected by the TUNEL method and immunohistochemistry. T cell apoptosis was induced by IL-2 deprivation, Fas Ag ligation, and exposure to TNF-α and nitric oxide. TUNEL+ leukocytes were few in control, CD, and ulcerative colitis (UC) mucosa, with occasional CD68+ and myeloperoxidase+, but no CD45RO+, apoptotic cells. Compared with control and UC, CD T cells grew remarkably 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 Fas- and nitric oxide-mediated apoptosis, whereas TNF-α failed to induce cell death in all groups. Compared with control, CD mucosa contained similar numbers of Bel-2+, but fewer Bax+, cells, while UC mucosa contained fewer Bel-2+, but more Bax+, cells. Hence, the Bel-2/Bax ratio was significantly higher in CD and lower in UC. These results indicate that CD may represent a disorder where the rate of T cell proliferation exceeds that of cell death. Insufficient T cell apoptosis may interfere with clonal deletion and maintenance of tolerance, and result in inappropriate T cell accumulation contributing to chronic inflammation.

Original languageEnglish
Pages (from-to)1081-1090
Number of pages10
JournalJournal of Immunology
Volume163
Issue number2
Publication statusPublished - 1999 Jul 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ina, K., Itoh, J., Fukushima, K., Kusugami, K., Yamaguchi, T., Kyokane, K., Imada, A., Binion, D. G., Musso, A., West, G. A., Dobrea, G. M., McCormick, T. S., Lapetina, E. G., Levine, A. D., Ottaway, C. A., & Fiocchi, C. (1999). Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. Journal of Immunology, 163(2), 1081-1090.