Statistics from Altmetric.com
See article on page 35
Intestinal inflammation results from derangement of those mechanisms of innate and acquired immunity which subtly regulate the local immune response.1 This is the case in Crohn's disease and coeliac disease, both characterised by marked mucosal lymphocyte infiltration, abnormal T cell activation, and upregulation of Th1 cytokines.2
In recent years another piece has been added to the entangled puzzle of intestinal inflammation. Apoptosis, a highly controlled process of cell death,3 modulates immune and inflammatory responses by limiting expansion of activated T lymphocytes and deleting autoreactive T cell clones.4 5 At the intestinal mucosal level, this process may be of particular relevance ensuring that physiological lamina propria T cell activation, due to chronic exposure to dietary antigens and exogenous pathogens, does not result in inflammatory tissue damage. Otherwise, defective T cell apoptosis may lead to a state of uncontrolled intestinal inflammation, and has been reported in coeliac disease6 and in Crohn's disease.7 8In the former, decreased lymphocyte apoptosis has been found at the level of the epithelial compartment,6 and this defect, favouring expansion of intraepithelial lymphocytes with an abnormal phenotype and a restricted repertoire, may precede the onset of refractory sprue9 or T cell lymphoma.10Unlike coeliac disease, in Crohn's disease the reduced susceptibility to undergo programmed cell death affects lamina propria T cells, which have been shown to be resistant to CD2 mediated apoptosis,7 and is possibly due to an imbalance of the anti- and proapoptotic regulatory gene products Bcl-2 and Bax.8
In this issue of Gut,11Itoh et al describe Bcl-2 family protein levels, ratios, and correlations in peripheral and lamina propria T cells isolated from patients with inflammatory bowel diseases (see page35). They expand their previous report8 by studying purified mucosal T cells, including measurement of Bcl-xL, and correlating Bcl-2, Bcl-xL, and Bax expression levels. Their results show that the low Bax level and consequent increase in the Bcl-xL/Bax ratio in lamina propria T cells may provide an explanation for the resistance of such cells to apoptosis in Crohn's disease. Although the subject of this paper is not entirely novel, these findings suggest new molecular insights into some of the possible mechanisms underlying mucosal inflammation in Crohn's disease, comprehension of which may provide the basis for potentially new therapeutic strategies.
If intestinal inflammation is accompanied by excessive immune cell survival in Crohn's disease, agents that have the capacity to increase T cell apoptosis, as shown recently in experimental colitis for blockade of interleukin (IL)-1212 or IL-6trans signalling pathway,13 may be particularly effective as a form of therapy for this condition. IL-12, a key cytokine in determining the outcome of the effector T cell response, may account for the predominance of the Th1 response in Crohn's disease.14 Produced mainly by monocytes and macrophages in response to bacteria, bacterial products, or viruses, IL-12 promotes Th1 cell differentiation. It has been shown recently that antibodies to IL-12, which suppress experimental Th1 mediated colitis, seem to exert their therapeutic effects by induction of lamina propria T cell apoptosis via a Fas dependent mechanism.12In addition, as T cells could require IL-12 to maintain levels of key intracellular antiapoptotic proteins, anti-IL-12 may restore lymphocyte apoptosis by downregulating Bcl-2 proteins (fig 1A).12
Concerning the therapeutic effect of anti-IL-6 receptor, Atreya and colleagues13 identified a direct pathogenic role for the complex of IL-6 and its soluble receptor (sIL-6R) in Crohn's disease and showed the therapeutic potential of disrupting this form of cytokine signalling. They demonstrated that lamina propria macrophages release sIL-6R which may complex with IL-6 and stimulate gp130 on the surface of intestinal lamina propria T cells, leading to a STAT-3 dependent cascade of antiapoptotic genes such as Bcl-2 and Bcl-xL and then to apoptosis resistance. By blocking the IL-6 trans signalling pathway, restoration of T cell susceptibility to apoptosis leads to suppression of Th1 mediated colitis in several animal models of chronic intestinal inflammation (fig 1B).13 Promoting lamina propria T cell apoptosis also seems to be the basis for the therapeutic benefit of antibodies to tumour necrosis factor α in active Crohn's disease15 but the mechanisms underlying this effect are at the present under investigation.
Recent studies on mucosal responses in T cell receptor (TCR) transgenic mice suggest novel strategies of downregulation of abnormal T cell survival by means of tolerance induction following oral antigen administration, and this may be a promising new approach for the treatment of Th1 T cell mediated experimental colitis and Crohn's disease.16 Oral administration of ovalbumin (OVA) to OVA-TCR transgenic mice results in induction of T cells producing transforming growth factor β which mediate oral tolerance in a process that is at least partly characterised by apoptotic deletion of Th1 T cells, both in Peyer's patches and elsewhere (fig1C).17
Taken together, these findings suggest that future strategies to defeat intestinal inflammation should include downregulation of excessive immune cell survival by targeting T cell apoptosis. However, further studies are needed to investigate the role of other cytokines involved in tissue injury, such as IL-15, which is highly expressed in Crohn's disease18 and seems to protect mucosal T cells from apoptosis.19 Only by defining the intricate connection of molecular mechanisms underlying defective T cell death will we be able to solve the problem of T cells surviving too long in Crohn's disease.
See article on page 35