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The hallmark of an immune response is the generation of a large new cohort of specific lymphocytes dedicated to the removal of the stimulating antigen. The protection afforded by the mobilisation of an army of potentially destructive cells comes at a price as these cells, if uncontrolled, may turn on the host. Thus when excessive immune activity occurs, immunopathology resulting from the “friendly fire” of inflammatory cells may compromise healthy tissue. To safeguard against this, mechanisms have evolved that remove the expanded population of leucocytes both at the end of the immune response, when antigen is eradicated, and also when excessive activation may be taking place.1 The ligation of a surface membrane molecule CD95 (Fas/Apo-1) on activated T cells by its ligand leads to apoptosis.2 Although once activated, the expression of the CD95 receptor is stable, the expression of CD95 (Fas)-ligand, which is also found on T cells, is transient and occurs after recent T cell activation. Thus when there are too many recently activated T cells in close proximity to each other, death rather than continued stimulation will occur, and this contributes to the downsizing of the local activated lymphocyte pool.
Although the expression of the CD95-ligand is largely (but not completely) restricted to activated T lymphocytes, many different cell types can express the CD95 receptor molecule.2 The paper by Ueyama et al in this issue (see page 48) shows convincingly that there is high CD95-ligand expression by T cells in lesions of ulcerative colitis but not Crohn’s disease. This, together with the observations that the CD95 receptor is expressed by epithelial cells in ulcerative colitis and apoptotic cell numbers are increased in colonic epithelia in some inflammatory bowel diseases,3 suggests that CD95/CD95-ligand interactions may be involved in the pathophysiology of ulcerative colitis. Although this is an attractive hypothesis, some caution is needed when interpreting the results. Although cells may show a high level of CD95 receptor expression, they are not necessarily susceptible to CD95 mediated death.4 In analogy, the presence of a gun is not harmful per se, it has to be loaded first. In order to be sensitive to triggering by the CD95 pathway, the appropriate downstream death signalling molecules have to be in place in the cytoplasm.4 For this reason, the presence of CD95 on epithelial cells in ulcerative colitis, which is only weakly expressed, does not necessarily mean that these cells will die upon contact with the ligand on T cells. One way in which to approach this in future studies would be to correlate the extent of apoptosis in the colonic epithelium of patients with ulcerative colitis with the local presence of T cells expressing CD95-ligand. Another way forward would be to compare the expression of CD95 and susceptibility to CD95 induced death in in vitro cultured gut epithelial cells from patients with ulcerative colitis and Crohn’s disease.
Although further investigation into the induction of apoptosis in the epithelium in patients with ulcerative colitis is clearly warranted, one should not lose sight of the central question raised in Ueyamaet al’s paper. As the CD95-ligand is transiently expressed on activated T cells, the presence of this molecule in ulcerative colitis but not Crohn’s disease is suggestive of recent, extensive T cell activation in the gut. What is the stimulus for the T cell activation in ulcerative colitis? The possibilities include normal tissue elements, suggesting a possible autoimmune defect as the basis of this disease,5 or foreign antigen/infectious agents. It is possible that the cells may even be proliferating in situ, a point which also requires further investigation. Irrespective of the ongoing stimulus, the intense T cell activation would potentially bring into play CD95/CD95-ligand associated homoeostatic mechanisms directed against the prevention of T cell overstimulation.5 Thus it may be also be possible to detect apoptotic T cells in these lesions. One unfortunate by-product of this normal control mechanism may be the non-specific, “bystander destruction” of the CD95 positive epithelium by cells expressing the CD95-ligand, as suggested by Ueyama et al. If subsequent studies confirm that this is the mechanism by which epithelial cell damage occurs in ulcerative colitis, then therapeutic strategies targeting this apoptosis inducing pathway may have to be considered.
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