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.
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.
If there is a suspicion that inflammasomes are related to a disease process that we find in our bodies, then we should at least think about using one of the over the counter and safe and well-studied inflammasome suppressors. As the research continues, we can hope that scientists studying in this area will show us more ways to dial down the frequency and the unpleasant symptoms and other consequences of autoimmune disease and autoinflammation.
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