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*
Division of Gastroenterology and
Molecular Cardiovascular Research Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan;
§
First Department of Surgery, Tohoku University School of Medicine, Sendai, Japan; and
¶
Department of Medicine, University of Toronto, Toronto, Canada
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-
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- failed to
induce cell death in all groups. Compared with control, CD mucosa
contained similar numbers of Bcl-2+, but fewer
Bax+, cells, while UC mucosa contained fewer
Bcl-2+, but more Bax+, cells. Hence, the
Bcl-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.
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