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 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-alpha 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-alpha 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.
Division of Gastroenterology, Molecular Cardiovascular Research Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
K
K
Ina
J
J
Itoh
K
K
Fukushima
K
K
Kusugami
T
T
Yamaguchi
K
K
Kyokane
A
A
Imada
D G
DG
Binion
A
A
Musso
G A
GA
West
G M
GM
Dobrea
T S
TS
McCormick
E G
EG
Lapetina
A D
AD
Levine
C A
CA
Ottaway
C
C
Fiocchi
D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D017209:Apoptosis / Q000276:immunology*; D018122:B7-1 Antigen / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002648:Child; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D003470:Culture Media; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018796:Immunoconjugates; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; C494826:BAX protein, human; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D003470:Culture Media; D018796:Immunoconjugates; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D016753:Interleukin-10; D009569:Nitric Oxide; D000069594:Abatacept