Inflammatory bowel disease (IBD) consists of two primary inflammatory disorders – Crohn’s disease (CD) and ulcerative colitis (UC). Given that family history is a major risk factor for the development of IBD, genetics are thought to play an imperative role in establishment of disease phenotypes. On a basic level, IBD is caused by an inappropriate and long-term immune response to commensal microbes. The reality is much more multifaceted, however, with the pathobiology including interaction of genetic factors “with microbial and environmental cues within tissue-specific contexts, the biological checkpoints involved, the selective decisions made during the course of disease and how plasticity of the biological response results in the capacity for different phenotypes” [1].
Due to the complexity of IBD, both CD and UC are currently labeled as idiopathic. Evidence exists that, in addition to genetic susceptibility, environmental factors such as sanitation, hygiene, smoking, and geography can yield mucosal inflammation. Infectious microbes and ethnic origin have also been reported to uniquely affect immune dysregulation and inflammation [2]. UC is distinguished by inflammation that is localized to the colon. Beginning the in the rectum, it spreads proximally. CD is distinct in that inflammation can occur in any part of the gastrointestinal tract, with the most common affected areas being the terminal ileum or the perianal region. Unlike ulcerative colitis, the spread is non-continuous and is frequently associated with “strictures, abscesses, and fistulas” [1].
Through the use of transcriptional profiling of circulating T cells derived from UC or CD patients, Lee et al. was able to identify CD8+ T cell transcriptional signatures that divvied patients into 2 distinct subgroups. UC and CD patients in these subgroups suffered from higher incidences of frequently relapsing disease and had elevated expression of genes involved in antigen-dependent T cell responses. Interestingly, no equivalent correlation was observed for CD4+ T cell gene expression [3].
Numerous other genes have been reported to play paramount roles in mediating these diseases. Given that abnormal intestinal permeability has been observed in IBD patients (as well as their immediate relatives), candidate genes involved in barrier integrity were investigated. Candidate genes that may regulate this process include CDHI, GNA12, and PTPN2. Truncated forms of E-cadherin (encoded by CDH1) have been associated with CD, with intestinal biopsies of CD patients showing inappropriate protein localizeationand cytosolic accumulation. Myriad transcription factors, such as HNF4A (regulates crypt cell proliferation), have been also been associated with IBD [1].
Autophagy, the catabolic process by which a cell degrades its own compartments, contributes both to the recycling and degradation of cytosolic contents and organelles. It also contributes to the removal of intracellular microbes and thus resistance against infection. ATG16LI, a gene essential for all forms of autophagy, appears to play a role in CD. Humans with the coding mutation T300A have an increased risk of Crohn’s disease and mouse models possessing defects in autophagy show abnormalities consistent with CD. Together these data all suggest an important role for autophagy in IBD [1].
In sum, perturbations of the host-commensal relationship caused by environmental and genetic factors lead to the pathogenesis of IBD. Consisting of CD and UC, IBD is marked by inappropriate immune responses to otherwise benign microbes and has been reported to involve alterations in intestinal permeability, autophagy, T cell gene regulation, and many other factors.
Citations:
1) Khor et al. Genetics and pathogenesis of inflammatory bowel disease. Nature 474: 307-217. 2011.
2) Baumgart et al. Inflammatory bowel disease: cause and immunobiology. Lancet 369: 1627-1640. 2007.
3) Lee et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest. 121 (10): 4170-4179. 2011
It is interesting to see that CD and UC are both considered idiopathic. To me, idiopathic is defined as something arising (in medicine) spontaneously or from unknown causes. Through these articles that were posted, it seems that we have a pretty good understanding that CD and UC are mainly caused by certain genetics and environmental factors (geography, sanitation, smoking, ect). Does this mean that we are getting farther away from thinking of these diseases as idiopathic and getting closer to knowing the exact cause of the disease? Just an interesting question I asked myself throughout this post. Very fascinating topic!!
ReplyDeleteThat's a very interesting point! I used the term "idiopathic" because one of the papers I referenced (Reference #2) referred to both CD and UC as such.
ReplyDeleteI found that to be odd as well, as I've only heard the term idiopathic used to describe disorders that were obscure and that doctors knew very little about. With IBD, although the root of the disorders is not precisely known, a wealth of information exists regarding what's going on with the disorders. AS you said, we know that there are both environmental (e.g. smoking) and genetic factors (e.g. genes encoding for intestinal permeability or for autophagy) that play important roles in mediating these diseases. We also know that CD and UC are the result of an excessive immune response to commensal microbes.
That being said I'm not sure if the authors in the second reference used the term appropriately.
These diseases are prime examples of complex etiology and pathogenesis, and illustrate well what is probably true of all diseases: they involve genetics, environment, and bad luck. Bad luck might be, in Crohn's, getting too many of the bad alleles of the 70 genes that show significant association with the disease.
ReplyDeleteI find the hygiene and environmental links with IBD very interesting. It reminds me of studies done linking allergies to the environment that you grew up in. For example, in the United States, if you grow up in a rural area rather than urban, you are less likely to develop allergies. Similarly, if you grow up in underdevoloped countries where certain parasites are common, it seems you are less likely to develop IBD. Still, I'm not quite ready to go out and eat a parasite in order to prevent IBD.
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