Molecular mimicry involves two or more unrelated molecules that mimic each other – for example, a viral protein may mimic a human protein. Why? A small portion of the viral protein may be very similar or identical to a small portion of the human protein. It is said that, in molecular mimicry, a protein “impersonates” another one.
If an antibody or a T-cell receptor is directed against that small portion of the viral protein, it will also bind the similar portion of the human protein. Sometimes this is called “mistaken identity”.
We can say that, in molecular mimicry, one protein impersonates another one, leading to a case of mistaken identity.
Photo Credit: C. S. Goldsmith and A. Balish, Centers for Disease Control and Prevention.
In our case, the viral protein is the hemagglutinin of the H1N1 swine influenza virus, and the human protein is hypocretin (also called orexin). Hemagglutinin is present on the surface of the influenza virus and is responsible for binding the cell that is being infected. Hypocretin is a neuropeptide produced by some of the neurons located in a brain region called the hypothalamus. It keeps us awake by sending appropriate signals to other regions of the brain.
In 20o9, the H1N1 swine influenza pandemic swept our planet. In 2010, an unexpected increase in narcolepsy incidence was observed in China — in areas in which the H1N1 influenza virus had spread the previous year. An increase in narcolepsy incidence was also reported in Europe — in children vaccinated with Pandemrix, a vaccine developed to control the swine flu.
The increase in the incidence of narcolepsy related to infections in China and to vaccination in Europe came on quickly, and since 2010, has steadily decreased — likely because the H1N1 swine flu pandemic ended and Pandemrix has not been used since.
A study recently published in Science Translational Medicine (December 18, 2013) shows that patients with narcolepsy — when given a seasonal influenza vaccine containing the H1N1 hemagglutinin — react by activating CD4+ T cells. The researchers isolated the activated CD4+ T cells from the patients’ blood, exposed the cells to hypocretin, and discovered that they reacted to this molecule.
These results provide evidence of molecular mimicry between H1N1 hemagglutinin and hypocretin and suggest that, in patients able to recognize the shared portion of these two molecules, an auto-immune response might lead to the loss of neurons that produce hypocretin. Although the specific mechanisms responsible for neuron loss are not clear, the researchers suggest that this process leads to narcolepsy, which develops when the neurons that produce hypocretin are destroyed.
The proposed working model is that narcolepsy occurs in people with a genetic predisposition, following exposure to an environmental factor that triggers an immune response directed to hypocretin. The 2009 H1N1 influenza virus was such a factor, and the genetic predisposition is due to the person carrying a specific form of one of the human leukocyte antigen (HLA) genes.
The researchers suspect that other viruses or pathogens could occasionally cause similar cases of mistaken identity. Indeed, molecular mimicry may not be as uncommon as once thought.
Copyright © 2014 Immunity Tales.
People get vaccinated for all sorts of disease: chicken pox, tetanus, measles, the flu etc. and the side effects of receiving these vaccinations are never really taken into account. Vaccines are made with confidence that the side effects are often insignificant and next to no risks. Nevertheless, there are unforeseen times when the vaccination causes an immune response not only to the pathogen but to healthy human cells, as seen with the H1N1 flu vaccine and neurons in the hypothalamus that produce hypocretin. I hope that with this discovery more care will be given in administering vaccines and vaccines will be placed under more testing to ensure that autoimmune responses are not elicited.
Vaccines do come with risks and side effects. I believe the question is not whether the risk is present, but if the risk of not taking the vaccine is greater than the risk of taking it. I agree with Tylah that people often take vaccines without remembering this key distinction. It really comes down to educating the general public about how vaccines work so that they are well informed when they make the decision to take/forego a certain vaccine. In the case of vaccines with H1N1 hemagglutinin, patients have the right to be informed of the molecular mimicry that has been reported.
I’ve heard of molecular mimicry in my microbiology course, but the phenomenon was presented to me as a way for pathogens to evade the immune response. By possessing a portion of a human protein, the pathogen is able to avoid an immune response because it is disguised as a self human cell. This was considered a defense mechanism. After reading the article, I think that it’s fascinating that molecular mimicry can also be a sort of attack mechanism. As stated, when antibodies and T-cell receptors target viral proteins, they also bind to a similar human protein, and this leads to a case of mistaken identity, which I guess is another way of saying autoimmunity. As we know, autoimmunity occurs when the immune system is unable to distinguish self from non-self, leading to a serious immune response, as described above in the cases of patients that developed narcolepsy after the infection or vaccination. I think more research should be done on our system’s immunological tolerance in order to better understand how our antibodies and T-cells can still trigger mistaken identity even after the selection processes during lymphocyte development. Nevertheless, it’s amazing and frightening at the same time that many viruses and other pathogens can use our own immune response against us.
I agree with your view on virus particles and how they attack the human body. I think that viruses are absolutely remarkable in that through specified mechanisms they are able to use our own immune system against us. It even makes sense that many viruses would behave in that manner to prevent the possibility of eradication. These mechanisms have likely evolved to accomplish such a response because the goal for any organism is successful reproduction. So the idea is scary, but it is very practical.
Wow, this is slightly alarming to me. Like previously stated, we all get vaccinations but sometimes we just don’t take into account the potential danger we are putting ourselves in when we choose to get them. This isn’t the first time that the topic of flu shots causing diseases has been a topic of discussion. A few years ago, a young lady claimed that a flu shot caused her to develop dystonia. Now, the validity of the story is in question because she is now “cured” but it did get everyone talking about possible side effects from the vaccinations. My question is, does this narcolepsy last for life now? I may have overlooked the answer but from reading, it seems that they get this H1N1 shot and develop narcolepsy. It’s a scary thought that you can take a seasonal vaccine and end up suffering for life. I also agree with everyone else that more care should be taken when developing vaccines. According to the WHO (World Health Organization), it takes approximately 5-6 months to develop a vaccine for a pandemic influenza outbreak. By the end of this time frame, the vaccines are ready to be administered. That is a relatively small time frame and they are developing this vaccine pretty quickly. It takes companies years to develop a new medicine but months for a flu shot vaccination; of course careless mistakes will be made. I think it really comes down to a lesser of two evils thing. You can take longer to develop a vaccine that you have had enough time to test thoroughly and have more people die or have a vaccine that “appears” to have few, less severe side effects and have more people live.
http://www.who.int/csr/disease/swineflu/notes/h1n1_vaccine_20090806/en/
Pandemrix, vaccine for the 2009 H1N1 influenza virus, was actually manufactured in Europe and is now banned from Finland and Australia due to the high case number of narcolepsy associated. This vaccine contains an adjuvant called ASO3 [1]. In general, an adjuvant enhances the response of the immune system to a smaller amount of antigen. More specifically, adjuvant prolongs the antigen presentation ability of MHC class 2 and therefore prolongs the action of CD4 T cells [2]. Since antigen presentation of MHC class 2 is more effective in the presence of adjuvant, and the fact that hemagglutinin of H1N1 influenza mimics hypocretin, vaccine in this case is both good and bad. It is good in a way that it is effective in fighting H1N1 virus. However, not only it kills H1N1 virus, Pandemrix vaccine also enhances the destruction of hypocretin-producing neurons. Because the structure of hypocretin and H1N1 hemagglutinin is very similar, MHC class 2 might mistakenly binds to hypocretin and presents it to the cell surface. Hypocretin-producing cells will become the ultimate target for this process because it obviously contains a lot of hypocretin and eventually will be destroyed our own immune system. In non-adjuvant vaccine, the mistaken antigen binding process might happen at a low rate but with an adjuvant vaccine, this process will be prolonged and might lead to a severe autoimmunity such as narcolepsy in this case. For instance, H1N1 influenza virus vaccine made in US never contains any adjuvant and therefore, there is less cases of narcolepsy observed compared to all countries that used Pandemrix as H1N1 vaccine.
References:
[1] http://www.cdc.gov/vaccinesafety/Concerns/h1n1_narcolepsy_pandemrix.html
[2] http://www.ncbi.nlm.nih.gov/pubmed/http://www.cdc.gov/vaccinesafety/concerns/adjuvants.html
According to “Swine Flu Connection Provides Clues About Narcolepsy,” there was a small increase in risk of developing narcolepsy after being administered the H1N1 flu vaccine (1). The article reports that Finland, which had the most dramatic change had one in 16,000 people that received the vaccine developed narcolepsy (1). However, narcolepsy is not a rare disease; the NIH states reports that one in 3,000 Americans suffer from narcolepsy with cataplexy (the loss of muscle control) and more cases that exclude this particular symptom are likely (2). Fortunately, the amount of media attention gained by the association between the H1N1 vaccine and narcolepsy will be useful in learning more about this disease that seem to affect a larger part of the population.
Computational studies at Stanford comparing structures of epitopes of hypocretin, a neurotransmitter involved in the regulation of the sleep cycle, and the H1N1 virus showed great resemblance, further substantiating the results reported in the Science Translational Medicine study (2). An interesting point is made by Stanford scientist is the uncertainty that molecular mimicry is alone responsible for the development of narcolepsy. In addition, the cells and mechanisms through which hypocretin-producing neurons are eliminated are unknown, as cells of the immune system circulating the blood do not have access to the brain. It is more likely that immune cells in the brain like microglia may be involved in this process.
References:
(1) http://www.sciencemag.org.ezproxy.gsu.edu/content/342/6165/1430.long
(2) http://www.ninds.nih.gov/disorders/narcolepsy/detail_narcolepsy.htm
(3) http://www-ncbi-nlm-nih-gov.ezproxy.gsu.edu/pubmed/23713377
It is indeed difficult to jump to conclusions just from observing a correlation between two phenomena. A study in 2011 most likely faced this dilemma. The study found several hundred people in China became diagnosed with narcolepsy during the same seasons when upper airway infections such as H1N1 influenza increased (1). It was possible that this correlation was pure coincidence, but the study above gives more insight on why this phenomenon occurred.
Another post on this blog summarizes that narcolepsy is an autoimmune disease, caused by T lymphocytes that react with hypocretin, a neuropeptide that keeps us awake (2). It references the same study above published December 18, 2013. You are correct in saying that molecular mimicry is not solely responsible for the development of narcolepsy. As stated above, narcolepsy occurs in those with a genetic predisposition. The H1N1 virus happened to be an environmental factor that triggered the immune response towards hypocretin.
Furthermore, cells of the immune system do have the ability to reach the brain. An example of this is multiple sclerosis, an inflammatory condition where myelin sheaths of neurons in the brain and spinal cord become damaged. One proposed mechanism of pathophysiology is a compromise in the blood-brain barrier, allowing T cells to enter and remain trapped in the central nervous system (3).
References:
1) Wood, H (2011). Sleep: narcolepsy associated with the 2009 H1N1 pandemic in China. Nature Reviews Neurology 7 (10): 537. doi:10.1038/nrneurol.2011.134.
2) Seized by Numbness: The Autoimmune Causes of Narcolepsy. http://immunitytales.com/seized-by-numbness-the-autoimmune-causes-of-narcolepsy/
3) Compston A, Coles A (April 2002). “Multiple sclerosis”. Lancet 359 (9313): 1221–31. doi:10.1016/S0140-6736(02)08220-X
It makes since that our body can cause itself the most harm. With something so simple, as to a mistaken identity, can induce a cascade of events which can eventually deteriorate us. Molecular mimicry is one of the most important factors in autoimmune diseases since these diseases are so strongly dependent on genetic make up. For molecular mimicry to work there has to be a specific strand of amino acids found in a protein that mimics another set of amino acids found in another protein. Although this is a rare occurrence given that there are only 20 different amino acids, when this does occur the outcome can be devastating. It makes since to how easily this can occur when the rite strand of amino acids are present. Our immune system reacts very swiftly and when an foreign invader is recognized by a T cell receptor, with the help of macrophages, the immune response is induced and activates many other immune system cells which will help in attacking and destroying the foreign invader even if it is not an foreign invader but has the rite amino acid sequence.
Having this as article as an example, I am curious as to why in development, manufacturers were not able to notice such correlation and molecular mimicry. With this particular example of H1N1 and narcolepsy, I think what truly needs to be noted is that H1N1 is a strand of flu virus. Every year a new vaccine is released to help prevent humans from the flu and that is because the flu is a virus that has a high level of antigenic variation. According to a study conducted at Harvard University, the flu virus is constantly mutating and thus new vaccinations must be developed to battle new strands(1). When developing new vaccines, my main concern is understanding how to combat these viruses in a way that would not disrupt the proteins that are naturally existing in our bodies. If this example proves that vaccines for the flu virus could lead to long lasting conditions like narcolepsy, has there not been more research to study flu virus pathogens and their resemblance to peptides? I guess my overall view of this can be expressed in two ways. First, how can vaccines be developed to reduce more long lasting complications? Secondly, will all viral particles have a “twin”? If so, I truly think that others have stated it is a simple decision weighing the risks of vaccination.
I like where JHernandez included the information about other parts of the body being possibly responsible. If what is stated above in the article ” the specific mechanisms responsible for neuron loss are not clear, the researchers suggest that this process leads to narcolepsy, which develops when the neurons that produce hypocretin are destroyed.” is true, then is the problem actually caused by molecular mimicry or could it really be caused by the vaccine causing neuron degradation?
(1)http://www.health.harvard.edu/flu-resource-center/vaccines-and-your-health.htm
I am not surprised at all that pathogens are able to perform this mimicry. They are changing and evolving at an alarming rate. I believe this goes along with the other article related to narcolepsy on immunity tales. The article notes that CD4 T cells are activated, which is different than what I previously thought. I was under the impression that if the body was attacked by a virus then the MHC class 1 molecules would be used in CD8 activation. Do I have the wrong understanding? Although the body’s cells aren’t viruses and are still being attacked so I’m guessing maybe that is why CD4 cells are involved? Autoimmune diseases are so life threatening so this raises the question- what is next for treatment? Maybe in the future there will be a development of a tagging system so the body knows not to harm itself. Although that sounds like a stretch, I would like to think that although the evolutionary process is slow, it may be possible.
The article states that there was a reaction in the person’s blood when given the vaccine, but it does not say that the person suddenly came down with narcolepsy. It seems everyone is taking this article as a negative look on vaccines, but I disagree. These patient’s aren’t necessarily getting autoimmune diseases from the vaccine, and I think the correlation is a stretch itself. Although there are issues with vaccines no doubt, I think they have clearly proven to be useful, and as long as we continue to be careful making them and testing them before publicly administering them, I think they will continue to do more help than harm.