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Found 7 results

  1. Celiac.com 01/16/2017 - Cerebellar ataxias can be caused by a wide range of disease processes, either genetic or acquired. Establishing a clear diagnosis requires a methodical approach with expert clinical evaluation and investigation. A team of researchers recently published a description of the causes of ataxia in 1500 patients with cerebellar ataxia. The research team included M Hadjivassiliou, J Martindale, P Shanmugarajah, R A Grünewald, P G Sarrigiannis, N Beauchamp, K Garrard, R Warburton, D S Sanders, D Friend, S Duty, J Taylor, and N Hoggard. They are variously affiliated with the Academic Department of Neurosciences, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK; Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK; the Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK; and the Department of Neuroradiology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK. All patients in the study were referred to the Sheffield Ataxia Centre, UK, and underwent extensive examination, including, where appropriate genetic testing using next-generation sequencing (NGS). The team followed-up patients on a 6-month basis for reassessment and further investigations, as needed. The team assessed a total of 1500 patients over 20 years. Twenty per cent of those patients had a family history of ataxia, with the remaining having sporadic ataxia. The most common cause of sporadic ataxia was gluten ataxia at 25%. They found a genetic cause in 156, or 13% of sporadic cases, with alcohol excess causing 12% and a cerebellar variant of multiple system atrophy causing 11% of sporadic cases. Using NGS, they obtained positive results in 32% of 146 patients tested. The most common ataxia they found was EA2. A total of 57% of all familial ataxias were supported by genetic diagnosis. The most common genetic ataxias were Friedreich's ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%) and mitochondrial disease (10%). The diagnostic yield following attendance at the Sheffield Ataxia Centre was 63%. Immune-mediated ataxias are common. Advances in genetic testing have significantly improved the diagnostic yield of patients suspected of having a genetic ataxia. Making a diagnosis of the cause of ataxia is essential due to potential therapeutic interventions for immune and some genetic ataxias. Gluten is a culprit is 25% of sporadic ataxia cases, and clinicians should keep this in mind when diagnosing patients, as many of these cases can be reversed with a gluten-free diet. Source: J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2016-314863
  2. Celiac.com 10/11/2016 - Celiac disease is an autoimmune disease in genetically susceptible individuals and is triggered by adverse immune reactions to gluten, a protein found in wheat and other grains. Researchers led by a research group at Finland's University of Tampere, led by Keijo Viiri, PhD, recently discovered a mechanism that triggers aberrant features in celiac disease and colorectal cancer. Disturbances in this mechanism seem to trigger certain symptoms celiac disease, and possibly in colorectal cancer. The research team's recent study offers new details on the pathogenesis of the differentiation defect of the epithelium in the small intestine in celiac disease. When people with celiac disease eat gluten, they suffer intestinal mucosal damage with villus atrophy and crypt hyperplasia. At the cellular level, epithelial cells are less differentiated and hyper-proliferative leading to the malabsorption of nutrients. Researchers discovered that a certain epigenetic mechanism, called Polycomb, governs the homeostasis between the intestinal stem cells in the crypt and the differentiated epithelium in the villi. Polycomb acts by silencing genes epigenetically by methylating histone proteins that are packing the DNA. "Polycomb is well-known for its function to regulate embryonal development. We discovered that Polycomb is also able to regulate the homeostasis of the small intestine in adults. The regulation of intestinal homeostasis is a tremendous task as the epithelium of the intestine needs to be replenished completely every 4-5 days," says Academy of Finland Postdoctoral Researcher and Principal Investigator Keijo Viiri. This study demonstrates that in people with celiac disease, dietary gluten triggers excessive activity of Polycomb leading to the aberrant silencing of genes necessary for the differentiation of villus epithelium and to the concomitant differentiation defect in celiac disease. Moreover, the study demonstrates that Polycomb target genes are also dysregulated in colorectal cancer, which suggests that aberrant Polycomb activity is common in intestinal diseases entailing a differentiation defect on the intestinal epithelium. From a clinical point of view, this work provides new insight into the pathogenesis of the intestinal damage in celiac disease and provides diagnostic markers for the disease. Since Polycomb regulates only genes imperative for development, this work is also instrumental to further understand the biology of the intestinal homeostasis. Source: ScienceDaily via Suomen Akatemia (Academy of Finland)
  3. Celiac.com 07/29/2016 - Celiac is an autoimmune condition, and along with other autoimmune diseases, scientists are beginning to have a larger context for understanding what could be contributing to its immune dysregulation. In the last decades we've seen diseases becoming prevalent now that look very different from the diseases of our ancestors. The American Autoimmune and Related Diseases Association lists 159 autoimmune diseases on their website (1), but most of these diseases are very new. In recent years, scientists began to identify and explore a new complex that was identified within our cells and belongs to our immunological line of defense. This new player is part of innate immunity, which is also called cell-mediated immunity. This is our body's rapid responder, and its approach to immunity is more like hand to hand combat. Its role is surveillance, and it uses generalized markers to identify something as an enemy and something the immune system needs to defeat. It looks for evidence of infection from bacteria, fungi, viruses and parasites but it also analyzes cellular debris. It is looking for any sort of danger signal that conveys the message that life is not normal as it ought to be (2). This analysis can even include looking for changes in pH (3). The innate branch of the immune system is dependent on cells that are called phagocytes, and these cells like to engulf small pieces of things they encounter, in a process called phagocytosis. Often these cells will be breaking down those pieces it engulfs and then will returning the nutrition it contained back into the extracellular space. After fragments from outside are internalized, cells needed a way to decide if what was engulfed should lead to a stepped up immune response. That's why it is not surprising that scientists recently discovered a whole network of molecules internal to these cells that form a complex called an inflammasome. There are various types of inflammasome that cover different biological niches (4). What this means is that, in response to what is deemed an enemy, a phagocytic cell will gather together a distinctive list of parts to assemble into an inflammasome, and then that inflammasome will produce specific cytokines called IL-1 beta and IL-18. These chemical messengers can then go and recruit more help. In contrast, antibody mediated immunity is more like having an air defense. The antibodies made by this part of our immune system function more like missiles that are sent out to find a designated target. Vaccines are designed for the antibody side of the immune response. Future recognition of a previous invader involves selecting a piece of protein, called a peptide, that is large enough to recognize. This side of our immune response forms a memory of that peptide so that in the future, our cells will use that memory to recognize that we have seen that germ before. If the germ is recognized from a previous infection, then the immune system can respond very quickly and with more hands on deck. The piece of the intruder's identity that will be remembered is determined by our HLA type, and that is determined by a section of DNA on our sixth chromosome. The vulnerability to celiac disease is defined by the genes that are behind the formation of HLA-DQ2 and/or HLA-DQ8. Scientists have known for many years that these two branches of immunity compete with each other and need to stay in balance. The chemical immune messengers called cytokines will shift our immune response between a dominance of cell mediated or antibody-mediated immunity. Until very recently, all the attention in celiac was on the antibody mediated branch whose major decision-makers are T cells, but even T cells can form inflammasomes (5). Scientists are now studying the innate immune response to gluten. Our innate immunity relies on a specialized call type called a phagocyte. Cells of this type of include monocytes, macrophages, neutrophils, granuloctyes, mast cells, dendritic cells, osteoclasts and even migroglial cells in the brain. Phagocytic cells will incorporate debris that comes close to them into a vesicle, and that is a sort of bubble with liquid and other contents inside. This vesicle is taken into the cell through a process called endocytosis. After that, this type of cell will quickly process the contents of that vesicle probably much faster than other cell types. This competence is likely why this type of cell is given the job of surveillance for invaders. It is also is useful as a tool for recycling things from the outside that they take in. Scientists prefer to call this set of cells the professional phagocytic cells. Other cell types can be enlisted for the job of phagocytosis but they don't have that role as their main purpose. That is why this different set is called the non-professional phagocytic cells and they may also form inflammasomes but may need more stimulation. (6). Scientists in the last decade have done experiments to learn how inflammasomes work. These intracellular immune complexes are assembled often in response to exposures to a type of molecule called a lipopolysaccharide that can be detected after engulfing the cell membranes of invading organisms. There are many other triggers, all recognized by their ability to tell us when something inside us is not as it should be. ATP, our body's energy molecule, when it is identified as coming in from the outside, can be a trigger for the inflammasome. Engulfing this sort of molecule suggests to our phagocytes that cell death events may have occurred in the environment of that cell (7). Some of our cells have been found to extrude nucleotides in self-defense, because leftovers from that kind of event may tell the inflammasome machinery that the cell is encountering a dangerous situation (8). This system recognizes that certain pathogens create holes in cell walls, so when a phagocyte encounters evidence of damaged membranes with holes in them, that alone can trigger a cell danger response that enlists inflammasomes. That means two popularly used medicines that kill fungus by inserting holes in their cells, Nystatin and Amphotericin B, have by themselves been found to create this danger signal even when there is no infectious agent. Doctors and lay people need to know that many signs that are usually associated with an infection, including fever, can occur when there is nothing infectious involved (9). Another inflammasome trigger is excess alcohol which can be very damaging when it triggers inflammasomes in the nervous system. (10) Another concern is environmental contaminates like asbestos and silica which have been studied the most when they are inhaled. (11) Crystals of uric acid associated with gout or other cell debris can also trigger the inflammasome, as can crystals of oxalate, which may be important to celiac disease since scientists have found higher levels of oxalate in celiac sprue. These crystals must reach a critical concentration to generate this cell danger mechanism in phagocytic cells (12). In the past, nobody really was aware that oxalate could have a major effect on the immune system outside of what it does in the kidneys. Scientists for so many years thought the kidney alone contained cells that oxalate could influence. That's why other cell types were not studied. At least now, we realize this narrow focus had been based on some premature conclusions. We should have known to look more broadly because there was so much evidence from Primary Hyperoxaluria, a genetic disorder where a defective liver produces oxalate that travels to the whole body, creating a condition called oxalosis. That's how we know that oxalate goes all over the body. For the longest time, nobody was measuring oxalate outside of kidney disease, even though there were a few exceptions, like in people after bariatric surgery, and in celiac sprue and in cystic fibrosis, and eventually, in autism (13). Because there already was a literature about oxalate in celiac sprue, when our project began, we started informing the public about these links on our website, www.lowoxalate.info. More recently we have written a series of articles about oxalate in this journal, discussing the science, and also practical issues about how to reduce oxalate while on a gluten free diet. That was working with knowledge we had then, but now we know that this issue of inflammasomes has been a part of the story we didn't know, but it holds great promise of possibly addressing why there could be complications in celiac sprue that do not resolve by merely going gluten free. Another trigger for the inflammasome is homocysteine (14). The pathway to recycle homocysteine back to methionine is called remethylation, and this process requires both methylcobalamin and the folic acid cycle. Others on internet groups have brought attention to polymorphisms in one of the relevant enzymes, called MTHFR. This system is also tied to the process of making sulfate, taurine and glutathione, because homocysteine can be routed that direction when the body is trying to resolve oxidative stress. Many of these steps require B6, and heme is also needed to direct homocysteine towards transsulfuration. The issue of excess homocysteine may prove to be more important to our non-professional phagocytic cells that are found lining our blood vessels, because these same vessels can also take up oxalate, creating a condition of vascular swelling called livedo reticularis (15). Issues with both homocysteine and oxalate have been associated with atherosclerosis (16). Did your child's pediatrician recommend giving your child Tylenol before his immunizations to make him more comfortable about his body's reaction to his shots? Scientists have now found that Tylenol not only depletes our body's ability to deal with the oxidative stress from immunization, but it also turns on the inflammasome (17). The inflammasome will skew immune defense away from Th2 adaptive immunity, and that is unfortunate, in this case, because the process of developing a Th2 response was the whole point of giving a child a vaccine. Our vaccines are designed to contain adjuvants that skew the immune response in the Th2 direction (18) but some adjuvants may not be working as expected (19). Researchers sometimes look for the evidence that someone has developed antibodies before they will call an immunization a success. That test will ordinarily not be ordered by a pediatrician, but instead, a child will simply later be given, by default, a booster shot. Is there any chance the recommendation of Tylenol or other inflammasome activators could have impaired the antibody response in some children? Certainly, the new research on inflammasomes might suggest that in children who fail to make antibodies after a vaccine, a look at what is happening with innate immunity could be in order before assuming that these systems are working normally. Are doctors testing antibody titres or doing other immune testing in children with celiac sprue? This may be more important if such a child has developed another autoimmune condition. Has gluten had other ways of affecting the immune response? We have known that gluten and proteins from milk, soy, and even spinach will form opioid peptides as they are broken down. Like other opiates, these active peptides can be addictive and would be able to skew an immune response (20).Opioids can also paradoxically activate inflammasomes in the spinal column which then may provoke, amplify, and prolong pain. (21) Other work showed us that activation at the same opioid receptors that drugs use can limit our absorption of the amino acid cysteine. This amino acid is needed by our bodies in order to provide glutathione, the primary cellular antioxidant that protects us from oxidative stress, and this is especially important to save us from neurodgeneration (22). Why is that important? The formation of glutathione can calm down a mitochondrion that is upset enough for it to be generating reactive oxygen species (ROS). Unfortunately, scientists recently learned that the ROS produced by a mitochondrion under such stress will also trigger the inflammasome. Having adequate glutathione is especially important when our bodies are coping with the demands of immune activity, as during illness or after immunization. Unfortunately, oxalate at those times may compete with glutathione for entry into the mitochondrion at the mitochondrial dicarboxylate carrier (23). Until very recently, we did not know that partially digested pieces formed from gliadin could trigger the formation of the inflammasome. This occurred more in peripheral blood mononuclear cells (PBMCs) from people with celiac sprue compared to healthy donors (24). The people who did this research may not have known that people with celiac tend to be higher in oxalate than other people, and they also may not have known that oxalate by itself has been found to trigger the formation of the inflammasome. People with celiac may need to be careful about avoiding both triggers for inflammasome formation. In a different context, another group of scientists discovered that PBMC's exposed to titanium salts made from oxalate caused immunotoxicity when other salts of titanium did not produce that toxic effect. That experiment tells us that oxalate does enter the type of cell that was also found to respond in celiac disease to these digests of gliadin by formation of the inflammasome (25). The well-studied vulnerability of individuals with celiac to antibody mediated effects of gliadin came from the adaptive arm of our immunity. The HLA type is definitely known to be relevant there, but it would not be relevant to an issue of cell-mediated immunity. That is why it is a puzzle that the authors of this study did not control for oxalate by matching the control and celiac subjects for the oxalate content of their cells. The differences they saw in response to the gliadin digest may have required higher levels of oxalate in those cells. Do we know? If that could be the case, then it becomes possible that the response they recorded in celiac cells might also happen in those who are higher in oxalate for other reasons, but who lack the HLA risk genes that are definitional of celiac. We simply cannot tell if the risk of inflammasome activation in their experiment involved having the oxalate content of these cells also working in some kind of synergism with gluten. It is important to note that here we are talking about oxalate that this type of cell may have accumulated earlier in its life or during its time in the blood. Here we are not talking about oxalate that someone may have just eaten. It is possible that an inflammasome-mediated function could explain why there are so many people who don't have celiac disease discovering that removing gluten from the diet makes them feel better. The academic community and others are still having a hard time believing this story (26), and cannot understand the recent popularity of gluten free foods in the general population. A different reason for thinking about a possible synergism between a gluten free and a reduced oxalate diet came from a recent poll done by the Oxalate Project at www.lowoxalate.info. Those results revealed that the majority of those who reported positive effects in their autoimmune disease by reducing oxalate had been extremely high in oxalate before they reduced oxalate. Curiously, 58% of those responding to the poll said they were also gluten free, but only 16% had celiac sprue. Those who were both gluten free and low oxalate reported a 10% higher positive effect from reducing oxalate than those who were not also gluten free. That could be important. Many scientists still think a standard American diet will keep oxalate below 200 mgs a day, but 84% of the individuals answering that poll said that they started out with levels of oxalate over 300 mgs a day. Recent changes in eating habits for high oxalate foods may have been the result of powerful advertising that has been telling people that high oxalate foods are the healthiest foods available. Anonymous poll data has no way to be verified, and that fact keeps us from assuming that we can derive information from this poll about oxalate's role (if any) in contributing to their autoimmune condition. Even so, the poll told us that out of all respondents, 73% reported a positive effect in their autoimmune condition by reducing oxalate, but those with celiac sprue (some who had other autoimmune conditions) did much better. 88% of them reported a positive effect on their autoimmune condition. That was actually a higher percentage than what was recorded for any of the other autoimmune conditions. Does that mean that it might be important for autoinflammatory processes to be careful about both gluten and oxalate? (27) We may learn the answer to that question as more people with these issues try both dietary changes together. Some scientists now are generating data that they feel supports the idea that excessive activity of inflammasomes could be related to the etiology of autoimmune disease (28). The changes that the inflammasome makes to our bodies can be harsh, and in fact, some scientists studied sepsis in animals and found that just by blocking inflammasome activity by various inhibitors, they could save those animals from a certain death. The irony is that the animals were still infected, but survived anyway. That means that what had been killing them was their immunological response to infection instead of the infection itself. This type of research is still very new, but it may change some of our assumptions (29). What interventions have scientists found that will suppress inflammasome activity? The good news is that a lot of their research has involved supplements that anyone can buy in a health food store, and some people were already using them for different reasons. One of those items is resveratrol. When it was first studied, it seemed to have been made out of red wine, mostly, but our project has discovered that commercially, the usual product is made from an herb called Japanese knotwood, which is known to be high in oxalate (30). The Oxalate Project has not yet tested the oxalate content of commercially available brands of resveratrol to see how much oxalate ends up in a capsule, but that testing is on its agenda. The supplement quercitin is also an inflammasome inhibitor (31). CoQ10 is another supplement that has become widely available in drug stores and health food stores because it is needed to correct a mitochondrial problem created by statin drugs. Fortunately, CoQ10 also inhibits the inflammasome, mainly by keeping the mitochondrion happier and better protected from the need to generate reactive oxygen species (32). A popular source of sulfur called MSM (methylsulfonylmethane) also was found to inhibit inflammasomes (33). So has its close cousin DMSO, a solvent that was once used as a delivery system for secretin, when it was proposed as a treatment for autism (34, 35). Another exciting inhibitor is 3-hydroxybutyrate, which is one of the two ketones (along with acetoacetate) that our bodies make in ketosis (36). Ketosis occurs when the body is not getting enough energy from carbohydrate, and it switches into a mode of burning fat, and that produces these ketones. Some people will try to induce this switch in metabolism on purpose, like those dealing with seizures who find the seizures are controlled with a ketogenic diet. If the change that this ketogenic diet accomplished was due to down regulation of inflammasome activity, that might bring new hope or strategies to mind for individuals where this diet treatment by itself failed. Such individuals may have had a different environmental component that was still activating inflammasomes in spite of their use of the use of the ketogenic diet. This mechanism may point to yet another reason that obesity, which may have come from excess consumption of carbohydrate, has been linked with inflammasome activation (37). We can hope that more investigation of other activators and other inhibitors for those with seizures might yield better success. Also, the association with ketosis may explain a previously overlooked benefit experienced by people who were exercising the discipline of fasting…the age-old tradition that comes from many cultures. These traditions are more striking when realizing that obesity can activate inflammasomes and inflammasomes are thought to be behind the roots of metabolic syndrome and diabetes (38, 39). Pharma does have some drugs already in its cabinet which scientists have found will inhibit inflammasomes. There are probably more such drugs in the pipeline and we may soon hear advertisements for this new class of drugs. Our Oxalate project has already begun to hear of some doctors and hospitals using the over the counter inhibitors resveratrol or coQ10 to successfully protect patients who were at risk for developing sepsis. More research obviously needs to be done in this area and this new frontier has become very attractive to scientists. One of the first big questions they may need to ask is whether our health care protocols in Western medicine have led to over-stimulating this arm of immunity by emphasizing killing strategies with antimicrobial therapies or other drugs that may leave crystals or other debris behind. Why might that have been a problem? Phagocytes are upset about cellular debris and disrupted membranes. Some scientists have been finding that our bodies may stay healthier by tolerating some infections rather than experiencing the excessive immune activity that comes from activating inflammasomes. It will take a long time for some of these scientific ideas to trickle down and begin persuading doctors to make changes in their prescribing habits for antibiotics and other antimicrobials. Some doctors and other practitioners are already finding that inflammasome inhibitors could be an appropriate adjunct therapy during antibiotics. Of course, since this is such a new scientific area to study, it may take years before proper clinical studies can be done to address all these issues. In the meantime, it seems wise for anyone prone to autoimmune disease to avoid triggers for inflammasomes that are easy to avoid. This would include things like being overweight, eating foods that encourage uric acid formation (and the risks known for gout). It could include situations that encourage the body to make oxalate and that could include deficiencies of B6 or thiamine, or excess use of Vitamin C. It could come from excess dietary oxalate. We also need to consider the use of drugs or supplements that are known to form crystals in blood, or Tylenol, or antifungals that punch holes in cell membranes. We need to be vigilant about our status for homocysteine. We need to be careful about our level of consumption of alcoholand our exposureto other environmental contaminants. In time, we will learn of many other triggers. 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  4. Celiac.com 08/09/2016 - Some researchers have suggested that gluten may not be the actual trigger of symptoms in non-celiac gluten sensitivity. Others feel that gluten is definitely the trigger, especially in certain cases. A team of researchers recently set out to evaluate patients with clinical non-celiac gluten sensitivity (NCGS), who presented with lymphocytic enteritis, positive celiac genetics and negative celiac blood tests. The team felt that the results would confirm that gluten is, in fact, the trigger of symptoms in this subgroup of patients. The research team included M Rosinach, F Fernández-Bañares, A Carrasco, M Ibarra, R Temiño, A Salas, and M Esteve. They are variously affiliated with the Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Terrassa, Barcelona, Spain, the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain, and with the Department of Pathology, Hospital Universitari Mutua Terrassa, Terrassa in Barcelona, Spain. The team conducted a double-blind randomized clinical trial of gluten vs placebo re-challenge on 18 patients over 18 years of age, HLA-DQ2/8+, negative celiac serology and gluten-dependent lymphocytic enteritis, and GI symptoms, with clinical and histological remission at inclusion. Eleven of the patients received 20 grams per day of gluten, while the seven others received a non-gluten placebo. The team measured clinical symptoms, quality of life (GIQLI), and presence of gamma/delta+ cells and transglutaminase deposits. The results showed that 91% of patients had clinical relapse during gluten challenge compared with just 28.5% after placebo (p = 0.01). Clinical scores and GIQLI worsened after gluten, but not after placebo (p<0.01). This study shows that gluten is definitely the trigger for symptoms in a subgroup of patients with clinical NCGS. After a gluten-free diet patients experienced positive celiac genetics, lymphocytic enteritis, and clinical and histological remission. Source: PLoS One. 2016 Jul 8;11(7):e0157879. doi: 10.1371/journal.pone.0157879. eCollection 2016.
  5. Celiac.com 02/15/2016 - Gluten sensitivities have been documented in some dogs, but now researchers have the first solid evidence that gluten is the culprit behind a movement disorder in Border Terriers known as Epileptoid Cramping Syndrome (CECS). There have been anecdotal reports that these dogs might respond to a gluten-free diet, but no clinical studies. This changed recently, when a team of researchers set out to assess the clinical and serological benefits of a gluten-free diet in Bornder Terriers with CECS. The research team included M. Lowrie, O. A. Garden, M. Hadjivassiliou, R.J. Harvey, D.S. Sanders, R. Powell, and L. Garosi. They are variously associated with the Davies Veterinary Specialists in Hitchin, UK, the Department of Clinical Sciences and Services of Royal Veterinary College in Hatfield, UK., the Department of Neurology at Royal Hallamshire Hospital in Sheffield, UK., the Department of Pharmacology, UCL School of Pharmacy in London, UK., the Department of Gastroenterology at Royal Hallamshire Hospital, Sheffield, UK., and with Powell Torrance Diagnostic Services in Higham Gobion, UK. The team evaluated a group of six client-owned Bornder Terriers with clinically confirmed CECS. The dogs all had at least a 6-month history of CECS, with their symptoms observed and confirmed using video, and each had exhibited at least 2 separate episodes on different days. The team tested the dogs for anti-transglutaminase 2 (TG2 IgA) and anti-gliadin (AGA IgG) antibodies at presentation, and 3, 6, and 9 months after the introduction of a gluten-free diet. They performed duodenal biopsy on 1 dog. Their results showed that, upon presentation, 6 of 6 dogs had increased serum TG2 IgA levels (P = .006), and 5 of 6 dogs had increased AGA IgG levels, compared to those of controls (P = .018). After 9 months on a strict gluten-free diet, 5 of the 6 dogs showed clinical and serological improvement with CECS. The one dog that had persistently high antibody levels apparently scavenged local horse manure, which contained gluten. However, this dog, too improved after the introduction of a strict gluten-free diet. So, all of the affected dogs eventually responded favorably to a gluten-free diet. To further demonstrate the connection, two dogs suffered relapses after gluten was reintroduced into their diets. In Border Terriers, canine epileptoid cramping syndrome is caused, and perpetuated by, an adverse reaction to gluten, and thus responds well to a gluten-free diet. The takeaway for owners of Border Terriers is to keep an eye on their dogs, and work with their vets if they suspect canine epileptoid cramping syndrome; which can be effectively treated with a gluten-free diet. Source: J Vet Intern Med. 2015 Nov;29(6):1564-8. doi: 10.1111/jvim.13643. Epub 2015 Oct 25.
  6. Neurology 2001;56:385-388. Celiac.com 02/15/2001 - According to a new study published in the February issue of Neurology, severe, chronic migraine headaches can be triggered in gluten-sensitive individuals who do not exclude gluten from their diets. The study examined ten patients who had a long history of chronic headaches that had recently worsened, or were resistant to treatment. Some patients had additional symptoms such as lack of balance. Dr. Marios Hadjivassiliou, from the Royal Hallamshire Hospital in Sheffield, UK, and colleagues tested each patient and found that all were sensitive to gluten. . The patients were tested and each was found to be gluten-sensitive. Additionally, MRI scans determined that each had inflammation in their central nervous systems caused by gluten-sensitivity. Results: Nine out of 10 patients went on a gluten-free diet, and seven of them stopped having headaches completely. The patients heightened immune responses, which are triggered by the ingestion of gluten, could be one of the factors causing the headaches. The other two patients who were on a gluten-free diet experienced significant relief, but not complete relief. Conclusion: According to Dr. Hadjivassiliou, removal of the trigger factor by the introduction of a gluten-free diet may be a promising therapeutic intervention for patients with chronic headaches. Further studies are needed to confirm Dr. Hadjivassilious preliminary findings.
  7. Celiac.com 12/31/2012 - In people with celiac disease, eating wheat, barley, or rye triggers inflammation in the small intestine. Left unchecked, this inflammation causes the gut damage that is associated with untreated celiac disease. Specifically, the storage proteins in these grains (gluten) trigger an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 as major genetic predisposition. Researchers actually have a pretty good understanding of this aspect of celiac disease, part of a process called adaptive immunity. However, there has been some research that suggests that gluten proteins might trigger an immune response in people who do not have celiac disease, and who do not carry the HLA-DQ2 or HLA-DQ8 genetic markers that predispose them to developing celiac disease. Such a response is part of a process called innate immunity, and is far less understood than the adaptive immunity process. The innate immune system provides an early response to many microbial and chemical stimuli and is critical for successful priming of adaptive immunity. To better understand the relationship between adaptive immunity and innate immunity in celiac disease, a research team recently set out to determine if gliadin digests might induce innate immune responses in celiac and non-celiac individuals. Specifically, they wanted to know if wheat amylase trypsin inhibitors drive intestinal inflammation, and if so, by what receptor mechanism. The research team included Yvonne Junker, Sebastian Zeissig, Seong-Jun Kim, Donatella Barisani, Herbert Wieser, Daniel A. Leffler, Victor Zevallos, Towia A. Libermann, Simon Dillon, Tobias L. Freitag, Ciaran P. Kelly, and Detlef Schuppan. They are affiliated variously with the Division of Gastroenterology and the Proteomics and Genomics Center at Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, with the Department of General Pediatrics and the Department of Internal Medicine I at the University Medical Center Schleswig-Holstein Kiel in Kiel, Germany, the Department of Experimental Medicine at the University of Milano-Bicocca in Milan, Italy, the German Research Center for Food Chemistry in Garching, Germany, the Hans-Dieter-Belitz-Institute for Cereal Grain Research in Freising, Germany, the Division of Molecular and Translational Medicine in the Department of Medicine I at Johannes Gutenberg University in Mainz, Germany, and with the Department of Bacteriology and Immunology at the Haartman Institute at the University of Helsinki in Finland. A number of earlier studies (Molberg et al., 1998; Anderson et al., 2000; Shan et al., 2002) have found HLA-DQ2– and HLA-DQ8–restricted gluten peptides that trigger the adaptive immune response in people with celiac disease. However, only 2–5% of individuals who show these HLAs develop celiac disease, which means that other factors, especially innate immune activation, are at play in the generation of celiac disease. Responsive innate cells are primarily macrophages, monocytes, DCs, and polymorphonuclear leukocytes that by means of their pattern-recognition receptors, such as TLRs, trigger the release of proinflammatory cytokines and chemokines, resulting in recruitment and activation of additional inflammatory cells (Medzhitov, 2007). Earlier studies (Maiuri et al., 2003) showed that peptides p31-43 or p31-49 from α-gliadin, that lack adaptive stimulatory capacity, triggered innate immune reactions by inducing IL-15 and Cox-2 expression in patient biopsies, and MHC class I polypeptide–related sequence A (MICA) on intestinal epithelial cells (Hüe et al., 2004). However, these studies have proven difficult to reproduce in cell culture, and researchers could not identify any specific receptor responsible for the observed effects. In a subsequent study, gliadin, in cell culture, reportedly triggered increased expression of co-stimulatory molecules and the production of proinflammatory cytokines in monocytes and DCs (Nikulina et al., 2004; Cinova et al., 2007). Two other studies (Thomas et al., 2006; Lammers et al., 2008) implicated the chemokine receptor CXCR3 in increased intestinal epithelial permeability upon gliadin challenge in a MyD88-dependent manner. However, those studies failed to reproducibly identify a specific gliadin peptide as the trigger. So far, no clear picture of the role of the innate immune system in celiac disease has emerged. In this study, the researchers show that members of the non-gluten α-amylase/trypsin inhibitors (ATIs), CM3 and 0.19, pest resistance molecules in wheat and related cereals, are strong triggers of innate immune responses in human and murine macrophages, monocytes, and dendritic cells. Their results show that ATIs activate the TLR4–MD2–CD14 complex and lead to up-regulation of maturation markers and elicit release of proinflammatory cytokines in cells from celiac and nonceliac patients and in celiac patients’ biopsies. They also show that mice deficient in TLR4 or TLR4 signaling are protected from intestinal and systemic immune responses upon oral challenge with ATIs. These findings define cereal ATIs as novel contributors to celiac disease. Moreover, ATIs may fuel inflammation and immune reactions in other intestinal and nonintestinal immune disorders. The findings of this study mean that the proteins in wheat may trigger immune reactions not just in people with celiac disease, but in people without celiac disease, and that these reactions may be actively contributing to the development of numerous other intestinal and non-intestinal immune disorders. That's a pretty big deal. Stay tuned to see how future studies elaborate these findings. Read the entire study in the Journal of Experimental Medicine. Source: J Exp Med. 2012 Dec 17;209(13):2395-408. doi: 10.1084/jem.20102660
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