Among the causes of IBD, the reason of stress seems to me too broad and therefore too hard to define. What is the ultimate standard for acute and chronic psychological stress? There are too many variations to be considered when we focus on this cause, in addition to the duration and intensity of different types of stress, each individual has different levels of tolerance when we deal with stress. All of these reasons revealed the difficulties when one tries to associate stress as the main cause of IBD.
The uncertainties of relating stress to IBD led me to research for other causes to this disease. There are many studies out there focused on relating IBD to genes. It seems as many scientists have known for a long time that IBD is related to genetics, and the evidence revealed that IBD tends to run in families. Different studies have shown the result of gene mutation on different genes and scientists believe that this disease is not caused by merely one particular gene but many different ones. New genes that are believed to lead to IBD are continually discovered and various genes mutations contribute to the different severe forms of the diseases.
One article[1] indicated that IBD that begins in childhood appears to be more severe than adult-onset IBD and is more likely to attack the colon than other areas of the GI tract. This fact motivated the researchers to study and analyze the genomes in childhood-onset disease, they found gene variants on both chromosome 20 and 21. The specific gene TNFRSF6B on chromosome 20 is known to participate in the tumor necrosis factor (TNF) biological pathway --- one of the cytokines that plays an important role of IBD. The researchers believe that with better more in depth knowledge of the disease pathway and all possible genes that are involved in forming IBD, it will increase the possibility of treating this particular disease by developing anti-TNF drugs that could be customized to each patient regarding to their own genetic profiles.
Although it is still not a well-understood disease to date, the ultimate goal for the researchers and scientists is to identify all the potential genes involved, their interaction with each other as well as environmental influences in IBD formation. Once the goal is achieved, the development for personalized treatments to patients will be possible.
For further reading on different studies regarding to IBD…
[1] http://www.medicalnewstoday.com/articles/119849.php
[2] http://www.medicalnewstoday.com/articles/138667.php
Robert N. Baldassano, M.D., director of the Center for Pediatric Inflammatory Bowel Disease at The Children's Hospital of Philadelphia.
Study Leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at Children's Hospital.
17 October 2009
16 October 2009
The difference between Crohn’s disease and ulcerative colitis…
Inflammatory bowel disease comes in different forms which mainly revolve around the intestines becoming red and swollen. Crohn’s disease is one form of inflammatory bowel disease that involves inflammation of the gastrointestinal tract. It is usually concerning the intestines but it also covers the rest of the GI tract. Symptoms of this kind of disease are various depending upon which part of the tract is affected. Many symptoms are associated with having a Crohn’s disease, and they include: abdominal pain, watery diarrhea, constipation, gastrointestinal bleeding, joint pain, and loss of appetite. The causes of this disease are still unknown but there is some relationship between this disease and the immune system. The immune system cannot differentiate between the host’s cells and foreign cell which results in an overactive immune response that leads to ongoing inflammation. Hence, Crohn’s disease is an autoimmune disorder. The disease primarily targets people between ages 17-35, and the risk factors include family history and smoking. There is no cure for this disease but doctors may prescribe some medications that may alleviate some of the symptoms. Removing the part that is affected surgically might also help.
Ulcerative colitis is another form of inflammatory bowel disease that mainly affects the large intestine and rectum. It has very much the same symptoms as Crohn’s disease except that the abdominal pain usually goes away after a bowel movement. Fever and weight loss are also associated with it. Moreover, this disease might stay inactive for a period of time and then progress quickly. The cause of this disease is unknown and can affect any group of people. Family history of ulcerative colitis plays a big role as a risk factor. The disease usually begins in the rectum and then spreads out to the entire large intestine. Severe attacks might cause the death of colon tissue, which can be removed surgically in a worst-case-scenario to remove the threat of colon cancer. No medications have been discovered that can cure the disease, but there are some which can control the condition and improve the symptoms.
Ulcerative colitis is another form of inflammatory bowel disease that mainly affects the large intestine and rectum. It has very much the same symptoms as Crohn’s disease except that the abdominal pain usually goes away after a bowel movement. Fever and weight loss are also associated with it. Moreover, this disease might stay inactive for a period of time and then progress quickly. The cause of this disease is unknown and can affect any group of people. Family history of ulcerative colitis plays a big role as a risk factor. The disease usually begins in the rectum and then spreads out to the entire large intestine. Severe attacks might cause the death of colon tissue, which can be removed surgically in a worst-case-scenario to remove the threat of colon cancer. No medications have been discovered that can cure the disease, but there are some which can control the condition and improve the symptoms.
15 October 2009
IBD vs IBS
While learning more about the exciting world of Inflammatory Bowel Disease, I learned that Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS) actually share very little in common, apart from affecting the bowel. I was under the impression that IBS could lead to IBD, or if you had IBS you were at a higher risk for IBD, or some such thing. But the mechanisms of the two diseases are so different that there is actually little overlap.
Inflammatory Bowel Disease causes the immune system lying below the mucosal layer of the bowel to over react to antigens passing through the lumen of the bowel. The two main types of disease causing this are Crohn's disease and Ulcerative Colitis, as mentioned in a previous blog. With Irritable Bowel Syndrome, nerve endings in the bowel are sensitive or "irritable", causing spasms, but otherwise the tissue in the bowel is normal. There are some similarities in symptoms, which is to be expected if both IBD and IBS are affecting the bowel's function. But IBS should never cause anemia, bleeding, permanent damage to the bowel or weight loss, which can be symptoms of IBD. While IBD is obviously an inflammatory condition, IBS is considered a "functional disorder", because it presents normal-looking bowel tissue. Thus, IBS can only be diagnosed by clustering symptoms (hence the term "syndrome"), while IBD can be diagnosed by taking a biopsy of bowel tissue. Obviously IBS is less serious than IBD, and will not put someone with the disease at a higher risk for colon cancer like having IBD can.
I just thought the distinctions were interesting, especially since I went into studying IBD thinking IBD and IBS were so similar.
Inflammatory Bowel Disease causes the immune system lying below the mucosal layer of the bowel to over react to antigens passing through the lumen of the bowel. The two main types of disease causing this are Crohn's disease and Ulcerative Colitis, as mentioned in a previous blog. With Irritable Bowel Syndrome, nerve endings in the bowel are sensitive or "irritable", causing spasms, but otherwise the tissue in the bowel is normal. There are some similarities in symptoms, which is to be expected if both IBD and IBS are affecting the bowel's function. But IBS should never cause anemia, bleeding, permanent damage to the bowel or weight loss, which can be symptoms of IBD. While IBD is obviously an inflammatory condition, IBS is considered a "functional disorder", because it presents normal-looking bowel tissue. Thus, IBS can only be diagnosed by clustering symptoms (hence the term "syndrome"), while IBD can be diagnosed by taking a biopsy of bowel tissue. Obviously IBS is less serious than IBD, and will not put someone with the disease at a higher risk for colon cancer like having IBD can.
I just thought the distinctions were interesting, especially since I went into studying IBD thinking IBD and IBS were so similar.
Infant Listeriosis Testing
An interesting question with practical application occurred to me while learning about the ontogeny of antibody responses. The question is this: If an infant tests positive for IgG to Listeriosis at 6 months of age, does this conclusively rule out the possibility that listeriosis was the cause of seizures and neurological damage apparent within 1 week after birth?
Listeriosis is a serious bacterial infection caused by Listeria monocytogenes. The bacteria can be found in soil, and can cause disease in some animals commonly used for meat and dairy for humans. Listeriosis is most commonly transmitted to humans via contaminated food, particularly uncooked meats and unpasturised dairy.
Listeriosis rarely affects people with a healthy immune response. However it may affect people of advanced age, pregnant women, newborns and people with weakened immune systems. Pregnant women are about 20x more likely to contract the disease than other healthy adults, and it is the risks associated with infection during pregancy, and during the post-natal period, that interest me most. An infected pregnant woman may experience only a mild, flu-like illness. Yet the infection can lead to miscarriage or stillbirth. Those infants that do survive have a reasonable chance of having seizures and neurological damage.
This question has direct relevance to my family because while pregnant with my youngest brother, my mother handled some goats on our property that were seriously ill with what looked very much like listeriosis. The goats had obvious neurological problems and major convulsions, and died. My mother's pregancy seemed healthy and went to full term. However a week after birth my brother began having convulsions and went on to display significant intellectual impairment. In retrospect he had a slight fever at birth, which went untreated. When my brother was six months old he and my mother were both tested for listeriosis. They both tested positive (though this was in 1989 and the test then had a higher rate of false positives than you might hope for). My brother had IgG against listeriosis. IgM was also tested, though we can't recall the result I would assume it was also positive.
When studying the ontogeny of antibody responses in IMMU7630 we learned that a foetus makes only IgM in utero. Maternal IgG crosses the placenta and so is present after birth. It has a half life of 3 weeks, so by 18 weeks after birth there should be only about 1% of maternal IgG remaining in the infant. The infant begins making its own IgG at around 12 weeks.
Without having studied the matter further, this suggests to me that an infant with IgG antibodies to listeriosis at 6 mo must have been exposed to lysteriosis after 12 weeks of age. This would rule out listeriosis as the cause for neurological damage. Yet is it possible that other mechanisms are in play? Could, for example, a B cell that began producing IgM to listeriosis in utero switch to IgG production as the infant's immune system matures? Are there other mechanisms that I have not yet considered?
I would be interested to hear your responses to these questions. It has piqued my curiosity, and I will certainly do some more research into the matter.
Listeriosis is a serious bacterial infection caused by Listeria monocytogenes. The bacteria can be found in soil, and can cause disease in some animals commonly used for meat and dairy for humans. Listeriosis is most commonly transmitted to humans via contaminated food, particularly uncooked meats and unpasturised dairy.
Listeriosis rarely affects people with a healthy immune response. However it may affect people of advanced age, pregnant women, newborns and people with weakened immune systems. Pregnant women are about 20x more likely to contract the disease than other healthy adults, and it is the risks associated with infection during pregancy, and during the post-natal period, that interest me most. An infected pregnant woman may experience only a mild, flu-like illness. Yet the infection can lead to miscarriage or stillbirth. Those infants that do survive have a reasonable chance of having seizures and neurological damage.
This question has direct relevance to my family because while pregnant with my youngest brother, my mother handled some goats on our property that were seriously ill with what looked very much like listeriosis. The goats had obvious neurological problems and major convulsions, and died. My mother's pregancy seemed healthy and went to full term. However a week after birth my brother began having convulsions and went on to display significant intellectual impairment. In retrospect he had a slight fever at birth, which went untreated. When my brother was six months old he and my mother were both tested for listeriosis. They both tested positive (though this was in 1989 and the test then had a higher rate of false positives than you might hope for). My brother had IgG against listeriosis. IgM was also tested, though we can't recall the result I would assume it was also positive.
When studying the ontogeny of antibody responses in IMMU7630 we learned that a foetus makes only IgM in utero. Maternal IgG crosses the placenta and so is present after birth. It has a half life of 3 weeks, so by 18 weeks after birth there should be only about 1% of maternal IgG remaining in the infant. The infant begins making its own IgG at around 12 weeks.
Without having studied the matter further, this suggests to me that an infant with IgG antibodies to listeriosis at 6 mo must have been exposed to lysteriosis after 12 weeks of age. This would rule out listeriosis as the cause for neurological damage. Yet is it possible that other mechanisms are in play? Could, for example, a B cell that began producing IgM to listeriosis in utero switch to IgG production as the infant's immune system matures? Are there other mechanisms that I have not yet considered?
I would be interested to hear your responses to these questions. It has piqued my curiosity, and I will certainly do some more research into the matter.
14 October 2009
MicroRNAs and the Immune System
This blog entry will introduce a fascinating class of post-transcriptional regulators (microRNAs!) and discuss some of their functional relevance to immunology within the context of a recent paper:
Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells.
Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E.
It would probably be difficult to find a biological process that is not regulated to some extent by microRNAs. Immunology is certainly no exception. MicroRNAs (miRNAs) are short, endogenous, single stranded RNA molecules, which combine with a protein complex to specifically downregulate gene expression by destabilizing, degrading, or blocking translation of target mRNAs. Because miRNAs act to maintain homeostasis of biological activities, their misexpression (either upregulation or downregulation, depending on the particular target) can result in disease. As we will see, miRNA misexpression can even contribute to autoimmunity. A better understanding of miRNAs and their individual functions could lead to therapeutic opportunities for many diseases. For example, miRNAs which target genes associated with disease could be either inhibited or increased to treat that disease.
What follows is an in depth example of how one microRNA (miR-155) interacts with the immune system and how this interaction was studied by Kohlhaas et al. As we have learned, regulatory T cells (Tregs) suppress the activation of helper T cells which is very important for self-tolerance… Without Tregs, we would have overactive immune responses and self-reactivity (autoimmunity).
The authors of this paper introduce their research by summarizing the role of Foxp3 as a transcription factor that regulates Treg differentiation and suppressor function. Foxp3 expression establishes the protein and miRNA expression patterns typical of a Treg cell. The deletion of miRNA processors in Treg cells causes mice to develop a wasting disease similar to that of Foxp3 knockouts. Basically, this tells us that Foxp3 regulates miRNA expression and that those miRNAs are responsible for Treg differentiation and function.
Although it is unknown which miRNAs are responsible for Treg function, the authors decided to study miR-155 because it is highly expressed in Treg cells and because Foxp3 binds its promoter. Interestingly, the number of Tregs in miR-155 deficient mice were found to be 2-3 fold lower than in normal mice. This decrease in Tregs, of course, could have been due to a decrease in their development, proliferation, or survival so the authors went on to investigate miR-155’s affect on these phenomenon.
Investigating miR-155’s role in development:
Rag2 knockout mice (which lack mature lymphocytes because they have no Rag2 and thus no V(D)J rearrangement) were injected with wild type or miR-155 deficient bone marrow cells. Analysis seven weeks later showed that wild type bone marrow cells were able to reconstitute the lymphocytes while miR-155 deficient bone marrow cells gave rise to a smaller number of miR-155 deficient thymocytes and splenocytes. These results demonstrate that miR-155 is required for Treg development.
Investigating miR-155’s role in proliferation and survival:
To determine whether miR-155 affects Treg proliferation and survival, the authors transferred either normal or miR-155 deficient Treg cells into lymphopenic mice (which lack lymphocytes). After five weeks, Treg cells in the spleen and lymph nodes were counted and there were similar numbers of the normal and miR-155 deficient Treg cells, meaning that miR-155 is not required for proliferation and survival of Tregs in vivo.
So far, the results suggest that miR-155 is required for thymic development of Treg cells but not for their proliferation and survival in the periphery. Next the authors wanted to investigate whether miR-155 was critical for the suppressive function of Treg cells.
Investigating miR-155’s role in Treg suppressive function:
In order to determine whether or not miR-155 deficient Tregs could still suppress helper T cells, the authors cotransferred CD4+CD45RBhigh T cells (which cause Th1/Th2 mediated colitis) with either normal Tregs or miR-155 deficient Tregs into immune deficient recipients. Mice which had received either normal Tregs or miR-155 Tregs were both protected from the colitis which would have otherwise been caused by the CD4+CD45RBhigh T cells. This result showed that miR-155 does not regulate the suppressor function of Treg cells.
In summary, the results of these experiments show that miR-155 is required for Treg development but not for the proliferation, survival, or suppressor function of Treg cells in the periphery.
Questions/comments are very welcome! Below are a few questions to get you thinking about miRNAs and the immune system:
1) How do you think miR-155 could contribute to the development of Treg cells? What might miR-155 target?
2) How could this information (that miR-155 is required for thymic development of Tregs) be used therapeutically?
3) What further experiments could be useful to study miRNA interaction with the immune system? What would you have done differently in any of the above experiments?
4) The authors explain that deletion of miRNA processors in Treg cells causes mice to develop a wasting disease similar to Foxp3 knockouts. Could this be due to a decrease in Treg cells (no miR-155)? Or is it the lack of other miRNAs (which ones???) regulating Treg function?
Extraintestinal Manifestations of Inflammatory Bowel Disease
Multiple other organ systems can be affected in IBD, including the bones and joints, skin, eyes, hepatobiliary system, lungs, and kidneys.These are called extraintestinal manifestations of IBD, and they can occur prior to, in conjunction with, or subsequent to active bowel disease. The overall prevalence of any extraintestinal manifestation in IBD patients ranges from 21%–40%.In most large studies of IBD, the prevalence of extraintestinal manifestations is higher in Crohn's disease compared with ulcerative colitis. There may also be racial differences in prevalence, with blacks having a higher risk for eye and joint manifestations, and Hispanics having a higher risk for skin manifestations, compared with whites.
Common Extraintestinal Manifestations of IBD
Musculoskeletal
* Peripheral arthritis
* Sacroiliitis
* Ankylosing spondylitis
* Osteoporosis
Dermatologic
* Erythema nodosum
* Pyoderma gangrenosum
* Aphthous stomatitis
Ocular
* Uveitis
* Scleritis
* Episcleritis
Hepatobiliary Disease
* Primary sclerosing cholangitis
Vascular
* Thromboembolic events
Renal
* Nephrolithiasis
Common Extraintestinal Manifestations of IBD
Musculoskeletal
* Peripheral arthritis
* Sacroiliitis
* Ankylosing spondylitis
* Osteoporosis
Dermatologic
* Erythema nodosum
* Pyoderma gangrenosum
* Aphthous stomatitis
Ocular
* Uveitis
* Scleritis
* Episcleritis
Hepatobiliary Disease
* Primary sclerosing cholangitis
Vascular
* Thromboembolic events
Renal
* Nephrolithiasis
Primary Sclerosing Cholangitis, an extraintestinal manifestation of IBD
Primary Sclerosing Cholangitis (PSC) is a chronic, progressive, cholestatic liver disease that is associated with IBD in approximately two thirds of cases. The diagnosis is often made in asymptomatic patients when abnormal liver function tests are noted in routine follow-up. If symptomatic, patients may complain of fatigue, itching, fever, right upper quadrant pain, and weight loss.
The traditional gold standard diagnostic test has been endoscopic retrograde cholangiopancreatography (ERCP), but noninvasive magnetic resonance cholangiography (MRCP) is increasingly used. It has been suggested that ERCP should remain the confirmatory test, given its higher specificity, or that perhaps it should be reserved for patients in whom the diagnosis is uncertain after MRCP. If an MRCP is negative and the index of suspicion is low, liver biopsy, rather than ERCP, may be the favored approach. Typical features at liver biopsy are periductal inflammation and fibrosis, bile ductular proliferation, and portal tract inflammation.
Ursodeoxycholic acid (UDCA) has been extensively studied in the treatment of PSC and is widely prescribed for this indication.
Steroids have not been shown to benefi t PSC patients, and trials of immunosuppressants have not demonstrated consistent benefi ts, though small studies of cyclosporine and tacrolimus have suggested that further investigation is merited. Tight strictures in the biliary tree can be treated endoscopically with balloon dilation or biliary stents.
Cholangiocarcinoma and colonic carcinoma Cholangiocarcinoma will develop in approximately 10% to 30% of patients with PSC , but to date there are no reliable means of identifying those at particular risk.PSC patients are also at particularly high risk of colonic dysplasia and cancer, and it is recommended that those with UC undergo yearly surveillance colonoscopy.
The traditional gold standard diagnostic test has been endoscopic retrograde cholangiopancreatography (ERCP), but noninvasive magnetic resonance cholangiography (MRCP) is increasingly used. It has been suggested that ERCP should remain the confirmatory test, given its higher specificity, or that perhaps it should be reserved for patients in whom the diagnosis is uncertain after MRCP. If an MRCP is negative and the index of suspicion is low, liver biopsy, rather than ERCP, may be the favored approach. Typical features at liver biopsy are periductal inflammation and fibrosis, bile ductular proliferation, and portal tract inflammation.
Ursodeoxycholic acid (UDCA) has been extensively studied in the treatment of PSC and is widely prescribed for this indication.
Steroids have not been shown to benefi t PSC patients, and trials of immunosuppressants have not demonstrated consistent benefi ts, though small studies of cyclosporine and tacrolimus have suggested that further investigation is merited. Tight strictures in the biliary tree can be treated endoscopically with balloon dilation or biliary stents.
Cholangiocarcinoma and colonic carcinoma Cholangiocarcinoma will develop in approximately 10% to 30% of patients with PSC , but to date there are no reliable means of identifying those at particular risk.PSC patients are also at particularly high risk of colonic dysplasia and cancer, and it is recommended that those with UC undergo yearly surveillance colonoscopy.
13 October 2009
IBD - Difference between Ulceratice Colitis & Crohn's Disease
Inflammatory Bowel Disease (IBD) refers to 2 chronic diseases that cause inflammation of the intestines: Ulcerative colitis and Crohn's disease. Although the diseases have some features in common, there are some important differences.
Ulcerative colitis is an inflammatory disease of the large intestine, in particular the colon. In ulcerative colitis the inner lining, mucosa, of the intestine becomes inflamed and develops ulcers. (Inflamed: lining of the intestinal wall reddens and swells. Ulcers: an open sore, which is a painful wound) Ulcerative colitis is often the most severe in the rectal area, which can cause frequent diarrhea. Mucus and blood often appear in the stool if the lining of the colon is damaged.
Crohn's disease differs from ulcerative colitis in the areas of the bowel it involves. Crohn’s disease most commonly affects the last part of the small intestine, known as the terminal ileum, and parts of the large intestine. However, Crohn's disease isn't limited to these areas and can attack any part of the gastrointestinal tract from the mouth to the anus. Crohn's disease causes inflammation that extends much deeper into the layers of the intestinal wall than ulcerative colitis does. Crohn's disease generally tends to involve the entire bowel wall, whereas ulcerative colitis affects only the lining of the bowel.
For more general information about IBD check out The American College of Gastroenterology website: http://www.gi.org/patients/gihealth/ibd.asp
Ulcerative colitis is an inflammatory disease of the large intestine, in particular the colon. In ulcerative colitis the inner lining, mucosa, of the intestine becomes inflamed and develops ulcers. (Inflamed: lining of the intestinal wall reddens and swells. Ulcers: an open sore, which is a painful wound) Ulcerative colitis is often the most severe in the rectal area, which can cause frequent diarrhea. Mucus and blood often appear in the stool if the lining of the colon is damaged.
Crohn's disease differs from ulcerative colitis in the areas of the bowel it involves. Crohn’s disease most commonly affects the last part of the small intestine, known as the terminal ileum, and parts of the large intestine. However, Crohn's disease isn't limited to these areas and can attack any part of the gastrointestinal tract from the mouth to the anus. Crohn's disease causes inflammation that extends much deeper into the layers of the intestinal wall than ulcerative colitis does. Crohn's disease generally tends to involve the entire bowel wall, whereas ulcerative colitis affects only the lining of the bowel.
For more general information about IBD check out The American College of Gastroenterology website: http://www.gi.org/patients/gihealth/ibd.asp
11 October 2009
Infliximab, a Drug for Crohn's Disease
TNF-α originates as a membrane-anchored precursor (pro-TNF) which is cleaved by the metalloproteinase TNF-α-converting enzyme (TACE), to then be secreted as a 17-kDa soluble protein. TNF-α exerts its effects through binding either one of the TNF-α receptors (TNFRs), TNFR1 or TNFR2.Infliximab(IFX) is a chimeric monoclonal Ig G1 (75% human and 25% murine) anti-TNF-α. IFX is able to bind soluble and membrane-bound TNF, and in vitro data suggest that it can induce T-cell apoptosis via complement activation or antibody-dependent cell cytotoxicity.Besides its action on immune and epithelial cells, TNF-α plays a crucial role in regulating cell adhesion molecule expression by intestinal endothelium and fibroblasts. Crohn's Disease (CD) patients undergoing IFX treatment down-regulate the expression levels of the vascular cell adhesion molecule (VCAM-1) and CD40 on the intestinal mucosal endothelium, thus inhibiting T-cell recruitment. In addition to TNF-α blockade and apoptosis induction, IFX exerts a wide spectrum of anti-inflammatory activities. For instance, IFX reduces the circulating levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). These two cytokines, proposed as markers of fibrosis and angiogenesis, are typically over-expressed in CD.
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