Hyperactive Immune System + Cytokine storms

Discussion in 'Fibromyalgia Main Forum' started by karinaxx, Mar 13, 2007.

  1. karinaxx

    karinaxx New Member

    i am still discovering new stuff and this article is close to the process i am suspecting happening in CFIDS/FM and other autoimmune deseases. i am curently checking into Vasculitis and Vascular Deseases.

    hope this will shed some light
    karina

    Overview

    Reported by Alan Dove | posted December 1, 2005

    When the body sustains injury, whether from physical force, chemical breakdown, or biological infection, the immune system springs into action. Ideally, its response is swift, severe, and strictly limited, quickly controlling the source of the damage and then backing off to allow the affected tissues to heal.

    Unfortunately, immunity sometimes spirals out of control, producing collateral damage that can range from irritating to horrific. Indeed, a hyperactive immune response is often more deadly than the initial insult that triggered it, and a major focus of modern immunology is understanding how to modulate these responses.

    Immunologists want to modulate hyperactive immune responses.
    On April 13, 2005, the Academy's Neuroimmunology Discussion Group met to share recent findings on shock and immune tissue injury. Featuring two speakers and a well-attended poster session, the evening meeting highlighted some surprising interactions and parallels between the central nervous system (CNS) and immune regulation. Though the CNS was once considered an immunologically isolated compartment, the new work adds to a growing body of data underscoring the close relationship between the brain and the immune system.

    Anthony Cerami began by discussing one of the more disturbing effects the immune system can have on the body: cachexia, the slow wasting away that accompanies many chronic diseases. A hallmark of such killers as HIV/AIDS, cancer, and parasitic infections, cachexia is mediated by the cell-signaling cytokine tumor necrosis factor factor-alpha (TNF-a). Though its name suggests that it would suppress tumor formation, TNF-a has been a disappointment as a cancer therapy, as stimulating cachexia usually outweighs any benefit the patient would get from increased tumor cell death.

    Having discovered TNF-a's cachectic activity, Cerami and his colleagues, first at the Rockefeller University and then at the Warren Institute, have spent the past several years studying this cytokine's mechanism of action. Damaged tissues produce TNF-a, and the protein triggers dramatic local inflammation and tissue death. Erythropoietin, better known for its ability to induce red blood cell production, also antagonizes the tissue-destroying activities of TNF-a. TNF-a, in turn, antagonizes erythropoietin. Cerami therefore refers to TNF-a and erythropoietin as the "Lucifer and Gabriel" of cytokines.

    TNF-a and erythropoietin are the Lucifer and Gabriel of cytokines.
    Hoping to bias the competition in favor of the good angel, the researchers have developed modified versions of erythropoietin that can be administered to patients with chronic diseases. Results from animal models suggest that these modified erythropoietins could help treat conditions ranging from stroke to heart failure, and the investigators are now preparing to start clinical trials.

    Kevin Tracey linked the discussion to the nervous system more directly, by revealing a surprising connection between the CNS and inflammation in other organs. Traditionally, immunologists have focused on the humoral, or blood-borne inflammatory response, and the local tissue-level inflammatory response, but a third branch of the inflammatory system has come to light in recent years.

    Dubbed the inflammatory reflex, this aspect of inflammation appears to be mediated by the vagus nerve, which connects the CNS to several major organs. Tracey and his colleagues at the Feinstein Institute for Medical Research have found that when inflammation occurs in the periphery, the brain can sense it and suppress it by sending signals through the vagus nerve.

    Having discovered this unusual reflex, the investigators tried to find the simplest way to stimulate it to suppress inflammation in an animal model of shock. They found that a short electrical jolt to the vagus nerve is potently anti-inflammatory, suggesting that an implanted device might do the job in patients. Even more surprisingly, carefully massaging the necks of the animals also suppresses inflammation and prevents shock.

    The brain can sense and suppress inflammation through the vagus nerve.
    At the molecular level, the inflammatory reflex appears to operate through nicotinic acetylcholine receptors, so drugs targeting those proteins might also be used to treat excessive inflammation and shock. The researchers are now designing clinical trials using all of these approaches, either in combination or separately.

    The two talks covered some of the latest work in the rapidly evolving field of neuroimmunology, where tight connections between the central nervous system and the immune system are now coming to light. Though immunology and neuroscience are arguably the most complex fields in modern biology, the new work suggests that treatments targeting this interface could have enormous clinical potential.

    Alan Dove earned his PhD in microbiology from Columbia University and is now a science writer and reporter for Nature Medicine, Nature Biotechnology, and Journal of Cell Biology. more >




    [This Message was Edited on 03/13/2007]
  2. karinaxx

    karinaxx New Member

    Cytokine storms
    Question: What do the following life-threatening medical problems have in common: avian flu, SARS, and anthrax? If you guessed "cytokine storms", you're correct. What was your clue?

    In view of the medical problems in which cytokine storms have been implicated, the topic is obviously of high importance. However, because they represent a malfunction in the immune system, which is quite complex, cytokine storms are presently not at all well understood, so it's hard to make definitive statements about them. Indeed, cytokine storms are more of a symptomatic condition and could occur in varying forms, involving a number of different mechanisms. "Storm" may be an appropriate metaphor, acknowledging a variety of mechanisms in a variety of circumstances. What different examples have in common is certain components of the immune system becoming seriously out of control and causing life-threatening problems.

    As background for this discussion, you might want to read (or reread) our previous article on T cells. One of the key players in this drama is the subtype of T cell known as helper T cells (also known synonymously as Th or CD4+ cells). As the name implies, Th cells assist other types of immune system cells in performing their function, so a number of other cell types may also be involved in a cytokine storm.

    Immune system cells (as well as various other cell types) communicate among each other with chemical messages known as cytokines, which are proteins or peptides (small proteins). The list of known cytokines is large and continually growing. To make matters worse, the nomenclature is not well-standardized and consistent, but some examples you may have come across (if you ever read medical literature) are various kinds of interleukins, interferons, and tumor necrosis factor (TNF).

    Although cytokine storms are not well understood, here's a general overview of what happens. Th cells appear to play a central role. The reason they are called "helper" cells is that they produce cytokines which in turn affect the behavior of other types of immune system cells. Which cytokines can be produced, and when, are quite variable, depending on circumstances. Likewise, which other immune system cells are affected, and in what ways, depends on the circumstances and the cytokines in the immediate vicinity. All these variables is what accounts for the complexity of the process.

    One possible effect of a cytokine is to cause proliferation of a particular type of cell. Some types of cells can even generate cytokines that cause proliferation of the same type of cell. A cytokine that does this is called an autocrine. Th cells provide an important example. Immediately after a Th cell becomes activated (upon enountering an antigen), the cell secretes interleukin-2 (IL-2), which acts on the Th cell to make it (and its progeny) divide rapidly. Clearly, such a positive feedback loop has the potential to start a runaway chain reaction, so there are also mechanisms that eventually slow it down or stop it – if everything goes as it should.

    Of course, Th cells also affect other cell types, such as B cells – the sort of immune system cell that produces antibodies. Cytokines from Th cells activate B cells and cause them to proliferate and begin to produce their antibodies. Other cytokines from Th cells may cause a different type of T cell – cytotoxic T cells (Tc for short) – to be activated and proliferate. At the name implies, Tc cells produce toxins that kill body cells (if they've been infected by a virus associated with an antigen that activates the Tc cell).

    Other cytokines can activate additional immune system cell types, such as macrophages and neutrophils. All this activity can lead to inflammation, which may cause a variety of problems of its own.

    Clearly, the immune system can do a lot of damage if it slips out of control. It's surprising problems don't crop up much more often than they actually do. In some of the research to be mentioned below, a few of the mechanisms which keep things in check will be noted. It may be possible to harness some of these as therapies to treat conditions where cytokine storms play a part – such as avian flu.

    In some of the news articles to be discussed below we'll learn about a few specific examples of known cytokine storms. Here are some additional general links dealing with cytokines and cytokine storms:



    Cytokine Storm – a primer at Flu Wiki

    Cytokines – notes from a course on introductory immunology

    Cell Interactions: Cytokines – lectures notes from a course on immunology

    Cytokines & Cells Online Pathfinder Encyclopaedia – extensive reference




    Avian flu and Spanish (1918) flu


    By now, is there anyone who isn't aware of avian flu, caused by the H5N1 influenza virus? You have probably also heard or read about another type of influenza virus (H1N1), which was responsible for the 1918 Spanish flu that may have killed as many as 50 million people. (An influenza virus is said to be of type HxNy depending on the variants present of two virus coat proteins, haemagglutinin (H) and neuraminidase (N).) In 2004 it was discovered that a normal flu virus modified to look like the 1918 virus could cause similar severe symptoms in mice, by inducing a cytokine storm. Background: here, here, here.

    Just a year later, in 2005, the entire 1918 virus was recreated in the laboratory. It proved to be, as expected, quite lethal to mice. Background: here, here, here, here, here, here, here, here, here.

    But the important question remained: Why was the virus so lethal? In September 2006 reports of the research appeared that gave a partial result:

    1918 flu virus's secrets revealed

    Dr John Kash, lead author of the study and assistant professor of microbiology at the University of Washington, said: "What we think is happening is that the host's inflammatory response is being highly activated by the virus, and that response is making the virus much more damaging to the host.

    "The host's immune system may be overreacting and killing off too many cells, and that may be a key contributor to what makes this virus more pathogenic."

    Dr Christopher Basler, a co-author from Mount Sinai School of Medicine, New York, said: "Our next step is to repeat these experiments, but deconstruct what the immune system is doing so that we can understand why it is reacting so strongly, yet failing to fight the infection."

    More: here, here, here, here.

    But notice that this report is still a little vague. It talks about a strong "inflammatory response" and how the immune system is "overreacting". As we know, the immune system is quite complex and has a large repertoire of responses for combating an infection. Is it possible to be more specific about what the system seems to be doing here? And does a similar effect occur not only in mice, but also in humans, or at least primates similar to humans?

    Answers to these questions appeared in January of this year, with details of experiments performed on macaque monkeys.

    1918 Killer Flu Tested on Monkeys

    The macaque experiment was supposed to last 21 days, but after eight days the monkeys were so sick – feverish, in pain, and struggling to breathe – that ethical guidelines forced the researchers to euthanize them.

    "There was some surprise that it was that nasty," University of Washington virologist and study co-author Michael Katze said. "It was the robustness of the immune system that helped victimize them."

    The virus is very good at replicating itself, said Peter Palese, chairman of the microbiology department at Mount Sinai School of Medicine in New York. Its effect on the immune system "triggers what one refers to as a cytokine storm," he said. Cytokines transmit messages among cells in the immune system. Palese wasn't part of the study but has worked on the resurrected virus before.

    No other flu virus is deadly to monkeys, and the speed in its spread and the overwhelming immune system response is similar to those in the H5N1 bird flu, Kawaoka said.

    So in fact, what this 1918 H1N1 virus appears to be doing is raising a cytokine storm that winds up destroying a lot of the victim's lungs. And that seems to be the same thing that happens with humans who have contracted the H5N1 avian flu virus. Nasty stuff.

    More: here, here, here, here, here.

    Obviously, there is an urgency to discovering countermeasures to lethal influenza viruses like H1N1 and H5N1. One biotech company has already announced testing of a drug, in rodents, which may be able to control excessive immune system reactions caused by flu virus infection. The account mentions one particular cytokine, IL-6 (interleukin-6), which has been associated with other immune system disorders, and which the experimental drug appears able to control.

    ImmuneRegen's Viprovex Demonstrates Immune Response Potential In Treatment Of Avian Influenza And Spanish Flu

    Cytokine storm occurs when an infected individual's immune system remains activated against the virus beyond the point of being helpful to where the immune response turns deadly. Persistent, highly elevated levels of pro- and anti-inflammatory cytokines induce a complex, dysregulated condition resulting in massive pulmonary inflammation and fluid accumulation, vascular dysfunction and eventually shock and death. Thus, in cytokine storm, the body's immune system fights to rid itself of the virus, but somehow escapes from the normal controls that prevent an overzealous immune system from killing its owner.

    As noted in the Nature publication, there are other disease conditions in which a hyperactive immune system is involved, and other drugs under development for treating those conditions might be beneficial in treating a pandemic influenza infection that could trigger cytokine storm. Specifically mentioned as central to regulation of the immune system, inflammation and hematopoiesis is the cytokine interleukin-6 (IL-6).

    Normal production and release of IL-6 is integral to functioning immune and hematopoietic systems, activating lymphocytes and increasing B cell antibody production, but its generation has also been implicated in a number of other diseases, such as rheumatoid arthritis, multiple sclerosis, Alzheimer's Disease and AIDS dementia.


    That's encouraging. But it's necessary to remember that studies of the efficacy and safety of new drugs in humans normally take the better part of a decade to perform. Even if this particular drug, or others like it, works in humans, we're hardly out of the woods yet as far as avian flu is concerned. In particular, the human immune system isn't necessarily all that similar to another mammal's, as the next section will demonstrate.

    Additional references:



    H5N1 Avian Flu Causes Dangerous Cytokine Storm – blog post at Future Pundit with more technical information on H5N1 and cytokine storms

    Monkeys die of 1918 flu. Should we worry? – blog post at New Scientist with a few more details and references (and perhaps a little too much tendency to see the research as some sort of frivolous curiosity on the part of the scientists)

    New flu drug calms the 'storm' – October 2003 news article from New Scientist about earlier research that investigated an experimental drug that seemed effective in dealing with a cytokine storm caused in mice by a modern analogue of the 1918 virus

    What is a Cytokine Storm? – makes the point that "cytokine storm" isn't a precise term, and may refer to different types of excessive immune system reactions

    Experimental Vaccine Protects Mice Against Deadly 1918 Flu Virus – Report of successful effort to produce a vaccine, effective in mice, against the 1918 H1N1 flu virus. More here.




    TGN1412 drug trial


    Undoubtedly you recall the story about a rather disasterous initial human trial of a new drug that, ironically, was intended to to treat rheumatoid arthritis and other autoimmune disorders. The trial took place in March 2006, and a report on what seems to have happened came out in August:

    Mystery over drug trial debacle deepens

    Doctors who saved the lives of six men who nearly died in a UK drug safety trial in March have revealed full clinical details of what happened during the first 30 days.

    However, far from explaining how the drug caused multiple organ failure in all six men, the results have simply added to confusion over how the drug affected their bodies.

    The healthy volunteers were given an experimental antibody drug called TGN1412 in its first human trial to test for safety on 13 March 2006 in London. Within the hour the six men injected with the drug were reportedly writhing in pain. Two others who were given a placebo were unaffected.

    The biggest mystery is why the men’s white blood cells – called lymphocytes and monocytes – vanished completely just hours after the drug was injected. This is the opposite of the effect observed in animal trials.

    Far from having a calming effect on the immune system, as intended and as was observed in animal tests, TGN1412 seems to have provoked a cytokine storm:

    All [experimental subjects] initially suffered from a so-called “cytokine storm” – a flood of inflammation-triggering chemicals pumped into the blood by activated white blood cells. This storm is what eventually led to multiple organ failure, the report says.

    The experimental subjects received a dose 500 times smaller than used in animals. But that wasn't enough of a safety margin.

    The injected antibody was unusual, because it was capable on its own of provoking lymphocytes, called T-cells, into becoming as active as they would be if they had to fight an infection. It normally takes two signals, not just the one provided by the antibody, to awaken T-cells. The antibody – known as a superagonist – was designed to be able to activate any type of T-cell without requiring the usual secondary signal. It works by binding to a receptor called CD28 on the T-cell surface.

    In earlier trials on animals, the antibody initially triggered multiplication of T-cells, but a specific subset, called regulatory T-cells, ended up multiplying fastest and taking control. The regulatory T-cells calmed the immune system. TeGenero hoped that this immune “calming” process offered potential therapeutic benefit, perhaps easing symptoms of diseases like rheumatoid arthritis, where normal T-cells attack the body’s own tissues.

    Unfortunately, the reverse happened. Around 60 to 90 minutes after the men received their injections, their bodies were flooded by a surge of inflammatory chemicals called cytokines, which combat severe infections like those seen in patients with blood poisoning. The cytokines caused severe inflammation.

    Note, in particular, that the antibody was expected to activate a special type of T-cells, regulatory T cells (Treg). Until just a few years ago, immunologists weren't even sure Treg cells existed. Fortunately, they do, because their purpose in life is to suppress immune system activation, to prevent activity from getting out of control. What is "supposed" to happen is that Treg cells provide a needed negative feedback to the system, to counteract the positive feedback loop driven by other types of T cells. Treg cells are being actively studied at present, and we'll write more about them in another article. Unfortunately, in the TGN1412 trial, things didn't go as expected.

    In December, another report came out that offered some hypotheses about why things went awry:

    Horror clinical trial in test tube recreation

    The new results presented today suggest that to send immune cells berserk, the antibody has to be tethered to a “surface” in the body rather than be free-floating. The team was only able to replicate the excessive cytokine response in the lab that the patients had experienced by effectively sticking the antibodies to a surface.

    But that doesn't seem to be the final word on the subject. About a month ago there was a further report:

    Researchers propose reason for severe side-effects of Northwick Park clinical trial

    The research shows that stimulating the molecule CD28 on cells that mediate the immune response, known as T cells, can have an adverse effect if these immune cells have been activated and altered by infection or illness in the past.

    The scientists found that when they artificially stimulated CD28 on these previously activated 'memory' T cells, this caused the cells to migrate from the blood stream into organs where there was no infection, causing significant tissue damage. CD28 is an important molecule for activating T cell responses and the TGN1412 drug tested on the human volunteers strongly activates CD28.

    Around 50% of adult human T cells are memory cells, having been activated by infections and illnesses during the course of a person's life. However, animal models, such as those used to test TGN1412 before tests were carried out on humans, do not have many memory T cells because they are deliberately kept in a sterile environment where they are shielded from infections.

    Here we see that yet another kind of T cells has been implicated – memory T cells. Undoubtedly there is still more of this story to be discovered. The immune system is a maze of twisty little passages...


    Septic shock


    One thing that is clear enough is that there must be negative feedback loops in the immune system, as well as positive ones. The latter enable the system to react quickly to serious infections. The former are needed to keep the system itself from spiraling out of control.

    The immune system disorder known as septic shock is another example of the system gone berserk. As mentioned in the Wikipedia article, our old friend, the cytokine IL-6, is among those implicated in this condition. Recent research (last November) has identified a specific gene that seems tasked to protect against septic shock:

    Gene Tied to Out-of-Control Immune Response

    A gene called auf1 seems to protect against septic shock in mice, a new study finds. Animals lacking the gene were more likely to undergo shock, suggesting that the gene helps keep the immune system's response to infections in check. Researchers hope to discover whether different forms of auf1 and related genes make people more likely to suffer autoimmune disease or life-threatening reactions to infections such as anthrax or flu.

    Infectious organisms trip specialized immune cells in the body and cause them to pump out proteins called cytokines, which produce inflammation and other hallmarks of infection, such as chills and fever. The body must carefully regulate its cytokine response, however, because "if it isn't turned off it can lead to septic shock and rapid death," says microbiologist Robert Schneider of New York University. Septic shock, which causes 9 percent of deaths in the U.S. each year, occurs when the immune reaction to a bacterial infection grows out of control, shutting down organs and sending blood pressure plummeting. Researchers think similar effects contribute to death from anthrax and pandemic flu.

    It appears that the gene codes for a protein which may interfere with messenger RNA that leads to production of cytokines IL-1ß and TNFa – thereby putting a brake on production of those cytokines if they are about to run amok.

    Undoubtedly, there are a number of chapters yet to be written in the story of how cytokines (and there are many more than have been mentioned here) are regulated. Stay tuned.

    More: New study finds on/off switch for septic shock

    -------------------------------

    Tags: immune system, cytokine, cytokine storm, bird flu, avian flu, septic shock, H1N1, H5N1, Spanish flu
    posted by Charles Daney • 2/23/2007 03:1
  3. Chootik

    Chootik New Member

    I haven't read anything from you in a while...

    I was wondering how you're doing wtih the Autoimmune? Are you still taking Ayurvedic meds?

    I have Hashimotos and have been doing so much research over the last few years for Autoimmune disease, but as I dont' have to tell you it's SO CONFUSING@ I'm still looking to see if there are any new supplements that can modulate the Immune system and fix the over activeness.

    Have you found anything like that so far?

    I appreciate your insights, it's great to have this board, at least we can find out more info than we get at the doctors offices.

    Chootik
  4. karinaxx

    karinaxx New Member

    hi there. I did not realize that there were others here spending so long time looking into Autoimmune stuff?

    the reason i have not posted much, is because i was travelling and had no connection to the net, but also having a lot of stuff to do and think about.
    no energy left.

    yes, i do have some ayurvedic stuff, but i am very reluctant to recommend it. side effects and i am not sure it is safe.

    i am so much worse in the moment and a lot of new symptoms poping up. i am not taking anything in the moment, to not slure the picture for the docs i am seeing.

    have you come any closer to a solution?

    karina
  5. karinaxx

    karinaxx New Member

  6. Chootik

    Chootik New Member

    Yes. I have been doing a lot of research but I discovered that I have Lyme a few months ago and have since been more focused on that.

    About Autoimmune, I have Hashimotos and for now it's under control. For a while I was having pain and a bit of swelling on one side of my Thyroid but when I stared taking Anti-Virals it suddenly got better! I had hight EBV and HHV6 levels.

    The things that I have found helpfull are Anti-Inflamatories.. like Omega 3 Fish oil, Flax seed oil, Selenium, and a lot of Antioxidants... mostly natrual stuff and some supps.

    Honestly I think there is a lot of reasearch going on but it seems like the medical community is not really going fast enough. I have heard of some South American herbs that help with Autoimmune but haven't followed up on that.

    What are your symptoms?

    Let's keep eachother posted on what we find out.

    I hope you get better soon :)

    Hugs..
    Chootik
  7. karinaxx

    karinaxx New Member

    i read about this south american herbs and i have something simmilar Ayurvedic.it is an Anti-inflamatory and it is kind of a immune surpressant if taken in short high doses.if i combine it with Aspirin i have an immediate effect, but i cant do it to long.
    It works, but i do have side effect like hiking my blood pressure up and giving me head aches.
    i am not sure how save it is, especially if we do have viral or bacterial infection going on.
    i will show the research done on it to Dr.Meirleir and see what he says.

    i am travelling to brussels today and see him tomorrow.

    your right about the Anti-inlfammatories and Vit.C
    i found an exellent source of Antioxidant in Amla juice (indian gooseberry),which is much better than the chemical vit. C.

    lets stay in touch
    take care
    karina

    i have MS like symptoms and getting checked in a few weeks in the hospital for vascular,CNS,MS . can tell you more about that, when its done.[This Message was Edited on 03/19/2007]