The Role Of Cell Induced Inflammatory Bowel Disease Biology Essay



Inflammatory bowel disease (IBD) comprised of Crohn's disease (CD) and ulcerative colitis (UC), are a group of chronic inflammatory disorders afflicting the gastrointestinal tract. CD is characterized by transmural inflammation afflicting any part of the gastrointestinal tract from mouth to anus, whereas UC causes predominantly inflammation of the mucosa and submucosa localized to the colon. The exact pathway of CD and UC pathogenesis is yet to be fully understood, but like most autoimmune and chronic inflammatory diseases, both are believed to result from the interaction of environmental, genetic, and immune factors.

Various environmental factors have been shown to be an essential component of the pathogenesis of IBD including smoking, diet, drugs, geographical and social status, stress, microbial agents, intestinal permeability and appendectomy. Although all these environmental factors have shown to have a correlation with the onset of IBD, the most indisputable example of the influence of the environment on IBD is tobacco use and the presence of specific microbial agents in the gut. Smoking increases the risk of CD, but has been shown to have a protective effect in UC. This suggests that there are distinct mechanisms involved in the pathogenesis of each form of IBD (Danese et al., 2004). Enteric bacteria have also been speculated as being triggers for the development of chronic gut inflammation. Over the years several microorganisms have been proposed as triggers for the onset of IBD including Listeria monocytogenes, Chlamydia tracomatis, Escherichia coli, Cytomegalovirus, Saccharomyces cerevisiae, and Mycobacterium paratuberculosis (Danese et al., 2004). Currently M. paratuberculosis is the most controversial since it causes Johne's disease, which is a chronic inflammatory enteritis of ruminants. The fact that Johne's disease is clinically similar to CD, has lead to the hypothesis that a mycobacterial species might be involved in the onset CD (Behr et al., 2008), although this has yet to be proven.

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As mentioned previously IBD results from the interaction between environmental, genetic and immune factors. Although environmental factors might be the triggers for the disorder, the predisposition to the disease is denoted by genetic and/or immune factors. The first IBD-associated gene, discovered in 2001, was the nucleotide-binding oligomerization domain 2 (NOD2) gene (Ogura et al., 2001; Hugot et al., 2001), and since then the understanding of the genetics of CD and UC has rapidly evolved. This has recently lead to the identification of over 30 CD-associated loci and a number of UC-associated genes (Achkar et al., 2009 and Barrett et al., 2009). Several of the genes identified, including IL23R, IL10, NOD2, ATG16L1 and IRGM, are involved in controlling intestinal barrier function, bacterial invasion, autophagy, or activation of the mucosal immune system (Achkar et al., 2009).

Although the pathways resulting in the pathogenesis of CD and UC are not completely understood, both are characterized by tissue damage resulting from an inappropriate or exaggerated immune response to antigens of the gut microflora. This loss of tolerance towards the enteric flora is mediated by an imbalance in inflammatory cytokine production. Cytokines are small peptide proteins produced by a variety of immune cells that are involved in cell-cell communication, proliferation of antigen presenting effector cells, and they mediate the local and systemic inflammation via the autocrine, paracrine, and endocrine pathways (Sanchez-Munoz et al., 2008 and Neuman et al., 2007). Over the years several cytokines have been identified as key factors in the pathogenesis of IBD, including TNF-α, TGF-β, INF-γ, IL-1, IL-4, IL-5, IL-6, IL10, and the more recently characterized IL-12, IL-13, IL-18, and IL-23 (Sanchez-Munoz et al., 2008 and Papadakis et al., 2000). Although both CD and UC share a common overresponsiveness to luminal antigens, they are two distinct immunological entities. CD is associated with a Th1 T cell mediated response, characterized by an enhanced production of IFN-γ and TNF-α. The Th1 differentiation is driven by IL-12 and IL-23, which in combination with IL-15, IL-18 and IL-21 will induce the stabilization of the polarized Th1 T cells (Sanchez-Munoz et al., 2008 and Monteleone et al., 2006). Contrary to this, in UC, the local immune response is less polarized, but it is characterized by CD1-reactive natural killer T cell production of IL-13 and Th2 cytokine production (Sanchez-Munoz et al., 2008 and Monteleone et al., 2006).

Recent studies have focused on identifying specific cytokines which could be used as targets for therapeutic treatments for IBD patients. In this editorial we will focus mainly on the IL-12 and IL-23 cytokines, which have been shown to be important mediators of a Th17 T cell induced IBD development.

Targeting IL-12 or IL-23:

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The importance of key cytokines in the pathogenesis of IBD has been intensely researched over the past few years. Although the inflammatory mechanisms involved in the onset of both CD and UC has yet to be fully understood, the importance of IL-12 family cytokines has been addressed in numerous studies. The IL-12 family cytokines are produced by antigen-presenting cells such as dendritic cells or macrophages in the human intestine, and have been shown to be implicated in the control of T cell differentiation and activation. This makes them ideal targets for T cell induced autoimmune diseases such as CD and UC. This family of cytokines is comprised of heterodimeric proteins with pleiotropic activities, including IL-12 (p35 + p40), IL-23 (p19 + p40), IL-27 (EBI3 + p28), and IL-35 (p35 + EBI3) (Neurath et al., 2009). So far the most intriguing IL-12 family cytokines have been IL-12 and IL-23, which have been studied and identified as being key cytokines in the auto-inflammatory mechanism observed in CD and UC (Neurath et al., 2009).

The first functional data proving the importance of IL-12 in intestinal inflammation was obtained by Markus F. Neurath and his team. They observed that anti-IL-12 antibody treatment resulted in the abrogation of the established experimental colitis in mice, when compared to mice that received a control antibody (Neurath et al., 1995). The concept of using IL-12 antibodies as a treatment for IBD was then used in a human clinical study of CD patients in 2004, which found that anti-IL-12 antibody was effective in treating the patients. The treatment was found to decrease the Th1-mediated inflammatory cytokines at the site of disease (Mannon et al., 2004).

Interestingly the anti-IL-12 antibody used for the previous described experiments was an anti-p40, which not only targets the p40 subunit of IL-12, but also that of IL-23. Thus, administration of the antibody neutralizes both IL-12 and IL-23, making it unclear which cytokine is responsible for the previously observed results. Furthermore, recent studies have shown that IL-12 and IL-23 drive two distinct immune responses. IL-23 has been shown to specifically stimulate memory CD4+ T cells, whereas IL-12 is a potent stimulator of naive CD4+ T cells (Oppmann et al., 2000 and Trinchieri et al., 1998).

Expression studies on CD and UC patients biopsies have revealed that IL-12 is up-regulated in both forms of IBD. Furthermore, as the disease progresses there is an increase in the presence of IL-12 receptors, suggesting that IL-12 mediated inflammation is stage dependent (Sanchez-Munoz et al., 2008 and Kugathasan et al., 2007). IL-12 has thus been identified as being involved in driving the adaptive immune response towards microorganisms in the intestine (Sanchez-Munoz et al., 2008 and Latinne et al., 2006). Thus blocking IL-12 might result in an abrogation of the inflammation, but it will most likely also result in an increase in infectious problems.

Numerous studies using animal models of colitis have been preformed targeting specifically p35 for IL-12 or p19 for IL-23, which have identified IL-23, and not IL-12, as the essential component for the manifestation of chronic intestinal inflammation in these models (Oppmann et al., 2000, Becker et al., 2003 and Yen et al., 2006). In animal models it was observed that IL-23 was inducing the production of the pro-inflammatory mediators IL-16 and IL-17 by activating a unique subset of T cells, Th17 memory T cells (Yen et al., 2006). Th17 cells have been identified as important mediators of the anti-microbial immunity at the epithelial-mucosal barriers. They produce cytokines which stimulate epithelial cells to produce anti-microbial proteins to clear out a variety of pathogenic microbes. Thus, a decrease in gut Th17 cells results in an increase in the hosts susceptibility towards opportunistic infections, while a significant increase in gut Th17 cells might result in an autoimmune disease.

Although this T cell subset develops independently from IL-23 via TGF-β plus IL-6 or IL-21, IL-23 is essential for the stabilization of their phenotype and effector functions (Maynard et al., 2009). In recent studies, it was observed that Th17 cell associated cytokines, surface molecules, and transcription factors were unregulated in CD4+ T cells isolated from patients with CD and UC, when compared to control samples (Maynard et al., 2009 and Kobayashi et al., 2008). Furthermore, it has been observed that in CD patients, mucosal CD161+ cells possessed an active Th17 phenotype producing IL-17 and IFN-γ when stimulated with IL-23. In contrast, in healthy individuals an additional priming step was necessary to enable IL-23 induced cytokine production (Kleinschek et al., 2009). These findings suggest that Th17 cells play a regulatory function in IBD pathogenesis and promote tissue damage, upon induction with IL-23.

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If all this data is taken together, it seems both forms of IBD, CD and UC, involve an aberrant expression of IL-23 driven Th17 tissue-homing memory T cells in the intestinal tract. Thus treatments for IBD should involve blocking the development of the specialized Th17 cells. The best targets for such an approach are IL-6 (a cytokine strongly related to an inflammatory immune response) and IL-23, which are cytokines that play a crucial role in Th17 cell differentiation and effector functions. A strategy previously proposed included the development of a vaccine against the IL-12 and IL-23 p40 subunit, which was shown to effectively treat IBD in mice models (Guan et al., 2009). There are several problems with the development of such a therapeutic treatment: 1) the vaccine must be administrated prior the onset of the disease and 2) the vaccine will permanently and drastically reduce the presence of IL-12 and IL-23 in the patient. Thus such a vaccine might have several side effects, including the patient's inability to drive the IL-12 mediated adaptive immune response towards microorganisms in the intestine. Furthermore, when dealing with vaccinations it is essential to know who is at risk of developing an IBD, something that has yet to achieved. Science has shown what genetic, environmental, and immunological factors are involved in the onset of IBD, but the presence of these factors does not necessarily result in the disease. As mentioned previously, to treat an IBD it would be necessary to target either IL-6 and/or IL-23. With the administration of anti-IL-23 antibodies the differentiation of Th17 cells is inhibited, while the administration of an anti-IL-6 antibody would affect the effector function of the Th7 cells. Thus both strategies are potential therapeutic approaches for IBD treatments.


IBD, comprised of CD and UC, are autoimmune diseases that have gained a significant importance over that past few years. The number of CD and UC afflicted people has dramatically increased, making the identification of a therapeutic treatment increasingly important. Studies have tried to identify the pathogenic mechanism involved in the onset of IBD and in so doing have identified genetic, environmental, and immune factors that play a major role in both CD and UC. A major breakthrough was attained when the administration of anti-IL-12 antibodies abrogated the disease in CD patients, suggesting that cytokine mediated immune system activation was crucial in the onset of IBD.

Although the anti-IL-12 antibodies were effective in treating IBD, it was later observed that these antibodies targeted both IL-12 and IL-23. Thus the effects observed in these studies could not be associated with only IL-12, but they suggested that IL-23 might also be crucial in the IBD pathogenesis. The following studies identified IL-23 as the key factor involved in the manifestation of chronic intestinal inflammation, rather than IL-12. It was identified that IL-23 activates Th17 memory T cell differentiation. A unique subset of memory T cells involved in mucosal immunity. Furthermore, both CD and UC patients have been shown to highly express Th17 cell associated cytokines, surface molecules, and transcription factors. This suggests that in both CD and UC IL-23 induced Th17 cells are crucial for the onset of the disease. Although current studies are targeting mainly IL-23, the effect IL-12 has has yet to be fully characterized.

In a future study animal models of both CD and UC should be treated with a specific anti-IL-23 antibody and/or a specific anti-IL-12 antibody. Such an approach, although time consuming, would help identify which of the two cytokines is involved in which form of IBD. Furthermore, such a study might shed some light on the specific roles each individual cytokine plays in the pathogenesis of CD and UC. It might very well be that both CD and UC are Th17 dependent, but the way in which these cells are activated results in the divergence of the immunological effects.


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