Appendicectomy: no beneficial effect in subjects with UC

In a study done by a group of Danish researchers on subjects who were admitted for ulcerative colitis there was no evidence for beneficial effects of appendictomy on admission rates in nationwide Danish hospitals in patients with UC. A cohort of patients who had an appendicectomy and their repeat admission for UC was studied. From 1981 to 1999, 202 subjects were identified as having an appendicectomy after their onset of UC. In this population based nationwide study with complete follow up, it was discovered that there was a moderate decline in hospital admission rates for UC after appendicectomy as compared to those who already had UC before their appendicectomy. The decline is not attributed to appendicectomy though because of the reference cohort showing a larger decline in admission rate.
Reference: Appendicectomy has no beneficial effect on admission rates in patients with ulcerative colitis; J Hallas, D Gaist, W Vach and H T Sørensen.
Furthermore, there is evidence released this week about the purpose of the appendix. An article published in the Journal of Theoretical Biology this week was referred to by the Associated Press. (http://news.yahoo.com/s/ap/20071006/ap_on_he_me/appendix_s_purpose) The article summarizes the work done by the researchers at Duke. It states that the purpose of the appendix (remember theoretically, unproven) is to act as a producer and store of good bacteria important in GI homeostasis. The article also goes on to describe the appendix as an outdated organ in the evolutionary timeline. The need for bacteria for the digestive system is not available to people from modern environments.
In conclusion, the study about the purpose of the appendix reinforces the study that an appendicectomy is not beneficial for patients with UC.

Genetics and IBD

I found the genetic aspect of CD (Crohn’s Disease) and UC (ulcerative colitis) that was explored in the articles entitled Inflammatory Bowel Disease: Cause and Immunology, Inflammatory Bowel Disease: Past, Present, and Future, as well as Translational Research in Inflammatory Bowel Disease to be interesting. Each of these three articles explored the genetics behind the susceptibility to IBD. Some genetic facts that were listed include: “Approximately 10-15% of IBD cases are familial, with familial clustering of CD and UC families occurring such that 75% of families are concordant for disease type, and 25% have both CD and UC within the same family” (Translational Research in Inflammatory Bowel Disease, Abreu, M., Sparrow, M.). Also, The research conducted with monozygotic twins revealed that there is a “pooled concordance in monozygotic twins of 37.3% for CD and 10% for UC” (Inflammatory Bowel Disease: Cause and Immunology, Baumgart, D., Carding, S.). It was also interesting to see that there was a less significant link between dizygotic twins (7% for CD and 3% for UC, according the same article). Furthermore, the linkage of genetic predisposition to CD was found to be stronger than that of UC. It was found that UC and CD have susceptibility regions on 12 chromosomes labeled as IBD1-9 and CARD15 (NOD2). Genetics appears to play a large role in susceptibility to IBD, however there are also links to environmental factors. The article Inflammatory Bowel Disease: Cause and Immunology mentions many environmental factors that have been shown to contribute to IBD, however it would be interesting to further understand why these factors increase risk. Also, for further research, I found an article entitled “Clinical Aspects and Pathophysiology of Inflammatory Bowel Disease” by Hendrickson, B., Gokhale, R., and Cho, J. from the Clinical Microbial Reviews. http://cmr.asm.org/cgi/content/full/15/1/79

Oral Tolerance and Retinoic Acid

Oral tolerance is defined as the induction of antigen specific immunological tolerance brought about by ingesting protein antigens(1). Ingested foods have unique antigenic characteristics the immune system is programmed to ignore, thereby allowing the body to tolerate the antigens found in food. In order to properly maintain immunologic homeostasis, oral tolerance is essential. Recently evidence has been published that identified a role for retinoic acid in oral tolerance(2-4). Retinoic acid is the physiologically active metabolite of vitamin A, retinol, and beta carotene found in the diet.
Two major players in oral tolerance are dendritic cells (DC) and T regulatory cells (T reg)(5). DC are responsible for antigen presentation, T reg cells are responsible for suppression of Th1, Th2, and Th17 (6) and thus are anti-inflammatory (the voice of reason in an otherwise reactionary society). Because of their function as immune suppressors, it stands to reason that T reg cells should play a pivotal role in any process of tolerization, including oral tolerance. Here are a few other details about T reg cells that are important for the rest of this summary to make sense: they need Transforming growth factor beta (TGF-b) to become a T reg cell from a naïve T cell, they primarily come from the thymus but they can also be produced peripherally, including the Gut Associated Lymphoid Tissue (GALT), and there is an integrin called a4b7 that helps them home to the GALT(5).
So here is what scientists have recently found: there is a specific population of DC (CD103+) in the GALT that makes TGF-b so that the naïve T cell that binds the antigens that it found in the intestinal lumen is stimulated to become a T-reg cell. The same DC’s also make retinoic acid and when these cells are treated such that they can no longer make retinoic acid, their capacity to induce differentiation into a T reg cell is diminished (3;4). In addition, a4b7 expression in T reg cells that were made in the thymus is dependent upon retinoic acid so it plays a role in the efficient trafficking to the GALT(2). Both of these findings, when taken together provide evidence that retinoic acid could play an important role in oral tolerance. What remains to be defined is whether it is necessary (meaning oral tolerance can not proceed in its absence); we know it is not sufficient (it alone can not induce oral tolerance).
Now to the part about why I care: disturbances in oral tolerance have been implicated as a possible mechanism in the pathogenesis of type 1 diabetes (T1D).* Some scientists have postulated that there are proteins in common foods that share antigenic determinants with the beta cells (bovine insulin is regularly vilified in the court of scientific opinion) and, when the very important process of oral tolerance is disturbed, the immune system becomes ‘confused’ and starts attacking beta cells(7). So could retinoic acid play a role? Before we can answer this question there are a number others that need to be answered first, I will introduce a few of them. First: is abnormal oral tolerance really the pathogenic mechanism in the auto-immune process that leads to T1D? Second: is retinoic acid necessary to the process of oral tolerance? Third: how are people with beta cell autoimmunity different with respect to their cells’ ability to utilize the dietary precursors of retinoic acid?
What other questions do you think are important when piecing this puzzle together?


* Type 1 diabetes is an absolute lack of insulin due to the immune mediated destruction of the beta cells (the insulin producers) in the pancreas.

Reference List

(1) Faria AM, Weiner HL, Faria AMC, Weiner HL. Oral tolerance. [Review] [321 refs]. Immunological Reviews 2005; 206:232-259.
(2) Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ, Benson MJ, Pino-Lagos K et al. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation.[see comment]. Journal of Experimental Medicine 2007; 204(8):1765-1774.
(3) Coombes JL, Siddiqui KR, rancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.[see comment]. Journal of Experimental Medicine 2007; 204(8):1757-1764.
(4) Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.[see comment]. Journal of Experimental Medicine 2007; 204(8):1775-1785.
(5) von BH, von Boehmer H. Oral tolerance: is it all retinoic acid?[comment]. Journal of Experimental Medicine 2007; 204(8):1737-1739.
(6) Cohen JJ. JJ Cohen's IMMU 7630 Class Notes. Ref Type: Generic
(7) Vaarala O, Vaarala O. Is it dietary insulin?. [Review] [50 refs]. Annals of the New York Academy of Sciences 2006; 1079:350-359.

Dendritic cells and T-cell responses in IBD

In reading several articles on the pathology of Inflammatory Bowel Disease (IBD), it appears that there are a few common understandings and possible avenues for therapeutics for both Crohn’s disease and Ulcerative colitis. Firstly, IBD typically manifests following an abnormal immune response to luminal (gut) flora. While the cause of this reaction has recently been linked to one or more genetic abnormalities, many researchers are focusing more on what occurs in the induced response, and how such a pathway can be halted before damage to tissue occurs. What appears to be common in both CD and UC is the activation of a T-cell mediated inflammatory response that results in the predomination of effector T-cells over regulatory T-cells, escalating the damaging inflammatory process. What also appears to play a part in both diseases is the presence and activation of dendritic cells. The dendritic cells of the gut reside just beneath the epithelial cells, and through the interstices of the intestinal epithelial cells, project long podocytes into the intestinal lumen for sampling of luminal antigens. After processing and presenting this data, either activation or tolerization results. Since it would be difficult to alter this sampling process, perhaps targeting the process following T-cell activation would be more feasible. In both forms of IBD, the expression of TLR-4 (toll-like receptor 4) is increased by dendritic cells following a helper T-cell response. This receptor, however, is distinct in its association with CD14, enabling presentation of lipopolysaccharide, which thereby induces influx of pro-inflammatory cytokines. If the expression of TLR-4 is common and frequent in both CD and UC, could the complex of this receptor with CD14 somehow be prevented? If so, could this lead to perhaps one method for disabling pro-inflammatory cytokine recruitment?

The Link Between Smoking and IBD

Inflammatory bowel disease is actually two different but similar diseases, Crohn's disease and ulcerative colitis. As said in the previous blog Crohn's disease generally tends to involve the entire bowel wall, whereas ulcerative colitis affects only the lining of the bowel. Even though it is still unknown what causes this uncomfortable disease, researchers have found that a number of factors such as environment, diet, and genetics can lead to this two diseases. While reading the article Inflammatory bowel disease: cause and immunobiology, I was surprised in discovering an interesting fact linking smoking and inflammatory bowel disease. It turns out that studies have shown that people who smoke are more likely to develop Crohn's disease than non-smokers. Smoker's tend to have a more aggressive form of Crohn's disease. However, when associated with ulcerative colitis it was shown that those who smoked were less likely to develop ulcerative colitis and tend to have a less severe course than those who do not smoke. Trials have shown that nicotine is of some benefit in ulcerative colitis due to increased mucus production and decreased cytokines. The article Smoking and inflammatory bowel disease. A case control study on gut.bmj.com goes into great detail about the results and statistics that they found when comparing smokers and non-smokers to UC and CD. They took non-smokers, ex-smokers and smokers and found that with heavy smokers, the risk of acquiring UC was lower than the non-smokers. Little is known on how smoking effects the location and the course of this disease. Although these studies have shown that smokers are less likely to have ulcerative colitis, smoking can lead to many other deadly diseases and is not advised as a therapeutic method for those who develop UC.

What is Inflammatory Bowel Disease?

That is was my first question when divulging into this week. The lay article from the Saturday Evening Post was a nice introduction. Not to be confused with irritable bowel syndrome, IBD is a fairly severe but typically non-fatal disease(such exceptions include a ruptured colon). Symptoms include upset stomach, diharrea, vomiting and nasuea. There are two types of IDB, ulcerative colitis and Crohn’s Disease. The differences are that UC affects the only the mucosa in the colon whereas Crohn’s has the potential to affect any and/or all of GI tract including the entire wall of the GI. The actual cause of the disease is unknown but it has a genetic trace in 10-15% of subjects with familial clustering of CD and UC families occurring such that 75% of families are concordant for disease type, and 25% have both CD and UC within the same family. (Abreu et al. Translational Research in Inflammatory Bowel Disease) Treatments are somewhat limited, typical anti-inflammatory protocol such as the use of prednisone is used often. However there has been some break through with the use of cyclosporine, a drug used in organ transplants as mentioned by the Saturday Evening Post. Overall, this disease is somewhat of a quandry. Hopefully a cure is in sight!