In the old TV series "Lost in Space" Will Robinson was warned by his robot when danger approached. In theoretical immunology a relatively new theory called the danger hypothesis is a challenge to the self vs non-self theory. In the danger hypothesis, broken down cell components alert the immune system. Thus, it is a self component which alerts the immune system Learn more about this hypothesis and answer the following questions.
1 What is the data that supports this theory?
2 Do you think this is a challenge to the self vs non-self theory?
3 Is it possible that PRRs are involved in the danger mechanism of immune activation?
DUE OCT 20
The danger model is a model of how the immune system functions and determines what to attack. In the danger model, the immune system is not concerned with foreignness but rather is more concerned with damage and is called to action by alarm signals given off by the injured tissues. APCs are activated by these “danger” signals causing the immune response. The fact that injured cells release their contents could be support for this theory. Cells killed through natural apoptosis usually do not release their contents because they are usually removed before their contents can be released. Cells that die through other means like damage from a microbe or injury, usually release their contents. These contents could be part of the danger signal that triggers the APCs and the immune response. The danger model has also been supported by the discovery of endogenous, non-foreign alarm signals like mammalian DNA, Hsps, RNA, and IL-1beta. Sometimes receptors bond to both exogenous and endogenous signals. For example, TLR4 is not only a receptor for LPS but also for Hsp70. Some research also shows that NOD receptors can respond to both injury and pathogen related problems within the body. Some have hypothesized that this is because TLRs and NODs first evolved as receptors for injury signals and thus microbes then evolved to use these receptors to their own advantage. From this view point PRRs would be very important because they would be the main cause of activation of the immune system through using danger signals. The self vs. non-self-model has some similarities to the danger model however it fails to explain things like why the body will attack a transplant but not a fetus or why the body can go through changes like puberty and still recognize itself. I think there is validity to both models and time and more research will show which is the more accurate model
ReplyDeleteShannon,
ReplyDeleteExcellent post. Thanks for getting this one started. DrFrancis
When cells undergo injury or stress their contents are released which signals T cells and an immune response. The Danger Hypothesis is a theory that claims that tissues or cells, when damaged send signals to the immune system that determine the appropriate immune response. Further hypothesizing suggests that this immune response is a direct result of the signal focusing the immune response primarily on the damaged cells/tissues and not foreignness of invading cells. The exception to this theory would be cells that have been killed via apoptosis. Those damaged cells do not release their cellular components and are removed from the system before they can instigate this immune response. The matter concerning a mechanism in which the damage cells signal an immune response remains to be seen.
ReplyDeleteIt has been suggested that patterns that on present on bacteria are not very different from the patterns present on the alarm signals released as a result of cell damage. As a result of this a kind of PRR can be used to signal this immune response. The TLR’s respond to the damaged cell components and act similarly to the PRR’s that recognize bacteria. There have also been discoveries showing that endogenous materials such as, mammalian DNA RNA, heat shock proteins (Hsps), interferon, and IL-1B, are shown to yield a signal. This could be due to the fact that a single PRR could bind to multiple materials. In example, TLR4 can bind Hsp 70 and LPS. This in turn suggests that PRR’s could have two design features. The first would consist of binding to pathogens. The second pertains to the PRR binding injury related signals. This theory in turn, does not dispel the “self vs. non-self” theory. Rather, it adds a new view into PRR’s and the immune systems response to damage. Both theories are valid within their own respects, but they need to be understood as a whole in order to gain the proper perspective on the immune system.
Tori,
ReplyDeleteExcellent. I like your new theory. DrFrancis
The main problem with the self-non-self model that paved way for the danger model has to do with T-cells. T-cells require APCs (antigen presenting cells) to chop up antigens and “present” them to T-cells in order to be activated. Polly Matzinger has theorized that antigen-presenting cells respond to danger signals from cells that have been injured, are undergoing stress, or have died from methods other than apoptosis. The alarm signals are sent by these cells and inform the immune system that an immune response is needed. T-cells respond not because of a distinction between self vs non-self, but rather because of a response to a danger signal from damaged cells.
ReplyDeleteWhile the danger theory answers some questions, it also leaves some unresolved. It does not explain why the immune system responds differently to different situations. Matzinger theorizes that tissues send signals to the immune system that differ depending on the required immune response. Perhaps this indicates that the danger model and the self vs non-self model are not mutually exclusive. Maybe elements of both of these models are correct and may someday contribute to a full and accurate model of immune system response.
The innate immune system is stimulated by PRRs (pathogen recognition receptors), which recognize patterns on the surface of antigens and alert the innate immune system. Proponents of this model do not see cell death in the absence of pathogens as the main stimulant of the immune system. But this theory does not explain why the immune system often rejects transplants that have not been compromised by bacteria or why the immune system can induce autoimmune diseases.
Matzinger has hypothesized that PRRs may be useful in the danger model. Hydrophobic portions of molecules are usually hidden on the inside of molecules to avoid contact with water. When cells are in distress these hydrophobic regions are likely exposed to the water environment, and these hydrophobic regions may alert PRRs that damage has occurred. These signals that the organs send are called DAMPs (danger-associated molecular patterns). She believes that DAMPs may be the answer as to why TLRs respond to both external and endogenous signals.
There are several exceptions to the self-nonself model of the immune system, which caused Polly Matzinger to develop the Danger Theory. Helpful bacteria in the duodenum and jejunum do not cause an immune reaction, although they are certainly foreign. Furthermore, sometimes the immune system does attack self with good consequences. Tumors are self, but they are fought by the immune system. Sometimes the immune system fights against autoimmune diseases, thus fighting its self. However, transplants work, meaning apart from the initial rejection reaction, the immune system does not attack non self.
ReplyDeleteTo escape these contradictions, Matzinger propsed the danger theory, meaning that the immune system doesn't just react to foreignness, but also to destruction caused by the pathogen. This would explain why some foreign, but helpful bacteria are allowed to live, while other dangerous but self cells are killed by the immune system. Matzinger said that the immune system responds to danger signals sent out by cells when they unexpectedly/unnaturally die. When these danger cells are sensed, antigen-presenting cells scoop up antigens that are in the "danger area" marked out by the alarm signal,and take the antigen to lymphocytes, who then produce antibodies against these antigens.
One problem with the theory is just the general vagueness of it. It is based on a danger signal whose mechanism has never been found. Another problem is the emerging research on T-cells. Mounting evidence is showing that special regulatory T-cells stop immune activity. This can explain why some immune reactions on self are allowed to continue while other immune reactions on non self bacteria are stopped.
Matzinger has shown that immune responses can be triggered by both PAMPs and DAMPs. DAMPs are danger associated molecular patterns that are not necessarily associated with pathogens. They are found in many endogenous molecules, such as IL-1B. Since endogenous molecules are secreted during traumatic events, Matzinger's hypothesis also gives an explanation for why trauma can cause the same inflammatory response as an infection does.
Viral immunologist Dr. Pinschewer and his colleagues found some novel evidence to support the "danger hypothesis." The key to their evidence was based on research and further exploration of interleukin-33 (IL-33). Interleukin-33 is a molecule which is stimulated and produced during infection. It also helps with fighting off parasites and asthmatic reactions. However when cells break and die off, the oversupply of IL-33 can spill from these cells and act as a possible stimulant for the detection of infection. One experiment by Pinschewer surveyed mice who are deficient in IL-33 compared to mice who are normal in their production of IL-33. They found that mice who were low in IL-33 were also extremely deficient in their supply of cytotoxic t-cells. IL-33 was proven to enhance the effectiveness of these t-cells by attaching to receptor proteins and "strengthening" the t-cells in their viral battles. During viral infection the IL-33 are located in the spleen where they are able to alert other immune cells, and provide as a complementary immune defense. This may all support the belief that a body will not just attack foreign things, but specifically foreign things that are destructive.
ReplyDeleteScientists have been drawn to this danger theory for a while now. While the danger theory has an element of complexity to it, it makes sense on an evolutionary scale for highly advanced eukaryotic organisms to use their own cells and tissues to respond to the high degree of diversity in pathogens, rather than somehow "evolving" receptors and immune systems to combat the huge range of pathogens in the world today. It makes sense to an evolutionist that these highly complex processes and redundancies we see in a human's immune system are all regulated by the complexity of inherent in a human's own tissues, rather than expecting a human immune system to adapt to thousands of unrelated and foreign life-forms. By assuming that immune responses originate from detection of like-cells being destroyed, evolutionists can assume that highly complex human immune systems have simply "piggy-backed" on earlier, less advanced prokaryotic immune responses that operate on similar principles.
ReplyDelete1. The discoveries concerning T cell response, and how they require an antigen presenting cell giving out correct signals to even begin to react to a pathogen invasion, seem to point to a deep layer of internal tissue signaling required to respond to pathogens. Scientists holding to the danger theory hypothesize that tissue cells are able to detect whether a cell has undergone a natural apoptosis event, or whether the cell suffered an unhealthy destruction at the hands of pathogenic substances. There appears to be some sort of mechanism within various tissues that not only minimizes damage received from foreign microbes, but also minimizes the collateral damage received from an immune response.
2. While the Danger Model carries weight as a new and progressive way of looking at the immune system, it seems to lack credibility in the details. Recent discoveries of regulatory T cells have really hurt the danger theorists, since regulatory T cells seem to be able to limit the immune response effectively without the assistance of tissue cells providing "danger signals". It seems clear that the more we know about our immune system, the more regulatory features we find that the immune system uses to regulate itself, without the need for damaged-cell signals. It seems better to me for scientists in the field to look at the immune system as an extremely complex series of redundant mechanisms that may not have one single model of response. A field as technical and complex as immunology may not be feasible in a system without multiple types of response-signal mechanisms.
3. I think it is extremely feasible that Patter Recognition Receptors are advanced to the extent that they are able to "see" tissue damage and initiate immune response accordingly. This, however, doesn't mean that PRRs ONLY interface with cell-damage. It seems clear that the immune system is forced to regulate itself on several levels, and PRRs are clearly not always in tune with tissue attack in the case of allergies and hyper sensitivity. The immune system seems to be able to interact to a large degree with specific pathogens also, and to gauge the appropriate immune activation level autonomously without continual cell-damage appraisal.
1. Data has been shown in what immunologists have discovered that T-cells depend on other cells to pick up and present the information from other cells so that T cells will respond. So the response for T cells depends on APC’s. This theory is in sync with what immunologists began discovering but Scientist Polly Matzinger took it further by coming up with an idea that APC’s respond to a certain danger signal by cells and most often when cells undergo injury, stress or aptosis. Some data that supports this theory is the study of tumors. Some tumors technically are not rejected because they are a mass amount of healthy cells, or rather self-cells. Tumors are an excess of cells that grow to the point of causing starvation or lack of nutrients of cells. When this lack of nutrients occurs this causes a form of apoptotic death. When the total number of dying cells goes into overload, the dead cells will begin releasing APC alarm signals. This will stimulate the T cell response. Matzinger points out that “there must be discrimination happening that goes beyond the self-non-self distinction. The human body changes over its lifetime and thus self changes as well. Therefore, the question arises whether defences against non-self learned early in life might be autoreactive later.” (http://arxiv.org/ftp/arxiv/papers/0801/0801.3549.pdf).
ReplyDelete2. I think that this is a challenge to the self vs non self theory in that it does provide good a new way to look at the immune system. It doesn’t necessarily respond to foreigness because there is good foreign bacteria in our gut that serves a purpose; rather the immune system reacts to danger. Matzinger points out how the immune system begins and then has its end functions but this model does not offer an explanation of why the immune system responds in different ways to different situations. Our immune system does respond to signals without cell death or cell injury, and this hurts the danger theory. No single theory can explain the function of the system as a whole. A newer study has suggested that there are regulatory T-cells which argues that immune activity is stopped by a special subset of T-cells.
ReplyDeleteI think that it is actually a great thought that PRR's could be involved in a danger signal. Certain regions of cell damage or injury can initiate these receptors, but I do agree with Richard in that these are not the only thing involved. This goes back to what I mentioned earlier that there is not one single theory or component that allows or body to "respond" but multiple components and signals.
i don't think that the danger theory will ever completely replace the self vs. non self theory. I think this is mostly because of the scientific communities lack of interest in explaining the immune system as a holistic system. Because of evolution, many do not believe that there is an overall design at all, but that the immune system is a combination of different systems all cobbled into one. If you're an evolutionist this is a more logical conclusion, but if you look at the actual evidence of the immune system, there is no doubt that there is an overall design.
ReplyDeleteThe immune system is known for its function of “self-nonself” discrimination. However recently, some scientists argue that the immune system detects danger. The scientists that support this view supports the danger theory. In the danger model, the immune system does not respond to foreignness, but to danger. In the danger model, everything that is foreign is not attacked. Danger is measured by the distress signals that are sent out when cells are damaged. An immune response according to the Danger Theory starts when a cell that is in distress sends out a signal. Antigens that are around the signal are captured by macrophages, and travel to local lymph nodes, which present the antigens to lymphocytes. The distress signals that are sent out by damaged cells establish a danger zone around itself.
ReplyDeleteI think it is possible that PRRs are involved in the danger mechanism of immune activation. The purpose of PRRs is to identify PAMPs, which are associated with microbial pathogens or cellular stress. As mentioned above, the Danger theory focuses on the immune system responding to danger, and danger is measured by the distress signals. These distress signals from cell are associated with PAMPs, which are recognized by PRRs.
1. The theory that cells can give off a danger signal that signals to other cells withing the immune system that something is wrong, has made the transition from being purely theoretical to practical. It requires that APC cells are activated by the small fragments of cells that have been broken down unnaturally suggesting there is something foreign causing the cell death. This theory has been supported by the discovery of endogenous signals including ones found in mammalian DNA and RNA. The fact that the body recognizes these signals suggest that maybe scientists have been looking at PRR's completely backwards. Maybe, instead of the molecules adapting/evolving to the shape of the pathogen, the pathogen has evolved/changed shape to fit the molecule which can sometimes help increase their chance for survival. It has been suggested that the PRR's were orignally able to determine the signals of injured cells, not just pathogen signals. This would play in its role in the Danger theory in that these receptors can recognize and direct the immune system towards the injured cell.I also agree with Kaylynn and Richard that the PRR's themselves are not the only things that are involved in this newly discovered/possible mechanism.
ReplyDeleteI dont think that the danger theory is a challenge to the non-self theory of how the immune system, but that they work together to reach the same goal. Both mechanisms want to rid the body of any foreign substance that is causing harm in whatever way that it can. The two models could have different recognition rates, meaning that the non-self theory could lead to a faster immune response because it can recognize the fact that the object is foreign right away, without waiting for the cell to become injured and secrete a signal. The Danger model seems like it has to wait until the infected cell breaks down and secretes its components which serve as signals to begin the immune response. agree with everyone else above that the danger theory will not replace the non-self theory, but that maybe there will be more discoveries about how the two actually work or benefit each other in the human body.
ReplyDelete