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Article: The Singh XMRV Patent The Next Cancer for XMRV? Prostate Cancer Results Validated/Progress

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Subsets, expansion and activation of myeloid-derived suppressor cells

http://www.springerlink.com/content/h32138704j864041/fulltext.pdf

Med Microbiol Immunol (2010) 199:273281

REVIEW

Subsets, expansion and activation of myeloid-derived suppressor cells

Eliana Ribechini Verena Greifenberg Sarah Sandwick Manfred B. Lutz

Historical overview

In the late 1970s, a formerly unknown cell population with suppressive features attracted scientific attention. These cells were identiWed in the bone marrow and spleen of tumor-bearing mice and in murine lymphatic tissue being able to suppress T-cell responses in vivo and in vitro [14]. They were termed natural suppressor (NS) cells. Further characterization demonstrated their involvement in tolerance induction by inhibiting different activities of the immune system. These cells were observed during enhanced hematopoiesis or intense immune responses, suggesting an involvement in regulating myeloid cell differentiation and controlling lymphocyte activation and expansion. Myeloid-derived suppressor cells (MDSC) are considered as critical for tumor immune escape mechanisms, as well as for chronic inflammation or infection due to their key role in regulation of immunity. MDSC are quite heterogeneous. Since their discovery these cells have been called among others, natural suppressors, immature myeloid cells (IMC) or myeloid suppressor cells (MSC). Although these names reflected the biology of the cells, this allowed confusion with mesenchymal stem cells (also MSC). Therefore, a uniform name was suggested as MDSC reflecting their origin and function [5]. Studies linking this population to diVerent diseases and pathologies have been increasing in parallel to the interest in unraveling their biology since they have been demonstrated to suppress T-cell immune responses by a variety of mechanisms [68].
 
That Singh is studying us is really cool. I'm looking forward to her study.

About the flu-like infectiousness of ME, it's thought to be communicable through casual contact like flu only at specific short times, like during the initial flulike (or other infectious--it can be a respiratory or gastrointestinal infection as well) illness.

And also, it seems some prerequisite, whether genetic factor, or from some trigger or contaminant from a vaccine, or hectic pace or other stress, or some other variable, is required in order to allow the chronic form to take hold. In other words, not everyone who contracts the flulike disease will get ME (or any related chronic infectious disease).
 
They would be like, "Thats the 6th cancer patient ive seen this week who has ME/CFS - thats odd."
But that hasnt happened.
Except that did happen. The cancer link is exactly why certain NCI researchers (some of whom now work for the WPI) were interested in the XMRV link with CFS in the first place.
 
Cannabis and ME/CFS

I am going with this model that alex has sketched: I think you're pretty much spot on alex, this model chimes very well with a whole load of...let's call them 'intuitions'...that I've had about all this for some years now.



To sum it up as I see it: the class of conditions including ME/CFS are suspected of being "autoimmune" disorders. They are, perhaps, "autoimmune" because actually some pathogen has invaded the body and 'got behind the defences', it's become part of the body and is now replicating, prompting an immune response. Thus "autoimmune" as a term is in a way a half-truth, because the body is trying to attack itself in a way, but really the part of itself it's trying to attack is the infiltrator, XMRV. In this confused state, the body ends up also attacking parts of itself as 'collateral damage'.

Further evidence for this whole model comes from the findings posted today about how cannabis switches off a particular part of the immune system. Put this together with the fact that in many of these rather mysterious conditions, patients report that the only effective pain relief comes from cannabis. If patients get pain relief because cannabis is switching off their immune system response, then that suggests that the pain was due to the immune response in the first place.

So our bodies are caught between a rock and a hard place, in a sense. Continually fight off the long-term effects of the pathogen (XMRV), and we stave off cancer but experience all the pain of the fight. Stop fighting the pathogen in the process of reducing ME symptoms and we deal with ME/CFS but allow the cancer to slowly develop.

The problem is that once XMRV has infected and taken hold, it is in a sense "part of us" now. We can fight off its virions as they replicate, which we are constantly doing - causing the symptoms we experience - but the immune system can't get to the root of the problem and deal with the XMRV-factories themselves - the bits which are now part of us, written into the DNA of infected cells.

Since we don't focus on it ever so much I'll just mention that factors that can provoke the XMRV-factories in is to start replicating include cortisol (stress), our body's anti-inflammatories, and hormones. I'm convinced the hormone factor explains why it's so much harder for women to fight off XMRV, because fluctuating hormone levels are going to be a regular factor that keeps bringing the root problem back into play, no matter how well your body has been coping.

To get a bit philosophical about it, the whole thing sounds like a bit of a metaphor of the dilemma of life in general: life is pain and suffering (samsara): the struggle to be, to continue to exist, is hard and painful. Give up, and let go of that painful struggle, and you die...

Crude Summary:
Cancer=Death
ME/CFS=The Fight For Survival
XMRV=One of the Main Enemies

Where we go from there, with that knowledge, I don't know, but the obvious thing to aim to do would be to identify the XMRV-infected cells in us and remove or destroy them.

Another strand of all this: regarding initial infection. I'm thinking now in terms of XMRV being moderately infectious and widespread, but being something that normally all our bodies would hope to be able to deal with. If we have our "eye off the ball" though, and our immune defences are down or over-stressed (due to things like severe viral infection, smoking cannabis, or severe stress) then XMRV can slip through the net: once it has done so, and infected us, then when our defences are back up our bodies can fight the replicating XMRV as normal (the constant immune activation that is ME/CFS), but they can't fight the source because it's now part of the body.

Loads more thoughts firing off from all of this now...like: how many of those whose ME did not start with acute viral infection (lowering immune response) were smoking cannabis around the time of onset? Of course that info is going to be a massive missing piece of the informational jigsaw, a piece of data that is going to be hidden or unreliable because most people won't want to admit to that because of the illegality.

One last note: putting this whole theory together with a number of connections in my own life to people who I know with ME and other ideopathic conditions who I suspect I may have been infected by, or who I may have infected, the whole thing pretty much fits like a glove. In each case of suspected transmission in my own life, the person who maybe got infected was either smoking cannabis or sick with flu at the time, and the person who maybe infected them was in particularly bad pain and thus likely to be more infectious. All fits really neatly.

Signing out now, but I bet I'll be thinking about all this for the next few hours...fascinating stuff...
I would like to note that cannabis is an NMDA/glutamate antagonist that buffers the glutamatergic excitotoxicity that occurs in ME/CFS. In essence, it is a neuroprotective chemical that is preventing further damage by excessive glutatmate in the CNS. It is no coincidence that most of the effective palliative meds found to date for ME/CFS and fibromyalgia are NMDA antagonists (whether selective or non-selective.) This includes dextromethorphan, opiates, cannabinoids, GABA agonists (such as Neurontin and Lyrica) and others. I hypothesize that there is a large subset (either causally related or by variation in individual physiology) that react extremely well to opiate medications and have a normalization of the CNS symptoms (hyperalgesia and micro-seizure related cognitive issues) with this medication and it appears extremely likely (based on the research that I have seen and my own experiences with these medications) that these medications are playing a direct role in mediating the cognitive and other CNS related symptoms.

It's makes a great deal of sense that the lack of endorphins would be related to the break down in sensory gating that we call hyperalgesia (most people think of endorphins as "natural painkillers" which is correct when produced in excess; but they also have a baseline function as part of our sensory gating system among other functions such as regulation of the digestive system.) This would also explain why ME/CFS patients lack an endorphin response to exercise. According to what I have read, the two main inhibitory systems for glutamatergic excess are the endorphin system and the GABA systems.

This excitotoxic damage also appears to be related directly to the cognitive issues. Some time ago I found an interview with an EEG expert who reported that he had found a micro-seizure in ME/CFS patients. The "alpha wave intrusion" he described matched what has been found in the alpha/delta wave sleep dysfunction studies. When one looks at the specific findings in neuropsych studies, the list of cognitive defects found matches exactly what one would expect if one were experiencing a micro-seizure approx. every 3 seconds or so. In essence, it's a very brief (1/10th of a second?; just a guess) type of absence seizure that is just enough to make it difficult to maintain attention and focus but not have to completely re-orient ones' self after each occurrence. It explains: the aphasia (the initial brain fart is the same but we have difficulty "triangulating" the word we are looking for due to the micro-seizure,) the lack of executive function and impulsiveness, and most tellingly, the dysfunctional startle reflex (the lack of "prepulse inhibition": normally when one is about to be startled and there is a "warning" or something that puts one on guard/vigilance, then one cannot be startled for at least 5 seconds. ME/CFS patients are not able to do this; which is why we seem "jumpy" sometimes. It makes a great deal of sense that ME/CFS patients are experiencing a micro-seizure in between the "warning"/prepulse stimulus and the actual startling event that prevents us from maintaining vigilance; in essence, we "forget" that we just heard or saw something that should put us into a vigilant state.) Right down the line, all of the cognitive symptoms match what one would expect with a micro-seizure of this type.

Further, it has helped me realize that there is a strong potential that a great deal of the CNS related symptoms are actually secondary to the main dysfunction related to cardiovascular disturbances that result in ischemia in the CNS. There is a great deal of research demonstrating that transient ischemia in the CNS results in excitotoxic damage and research studies have demonstrated elevated glutamate and lowered levels of endorphins in ME/CFS patients.

Also, my own personal experience with the "raggedy andy/ann" fatigue has shown me that this hypothesis is most likely correct. When I used to go through this "fatigue state" (which is like calling a grand mal seizure a "hiccup") I had the, "my-brain-is-connected-to-a-channel-changer-that-someone-else-is-controlling-and-has-stuck-it-on-autochange-every-couple-of-seconds" effect and I can only surmise that this is the micro-seizure made much more intense and obvious by the drop out in blood pressure occurring with the "raggedy andy/ann fatigue" (since it appears that this state occurs cyclically in the less severe and is metabolically mediated and reactive to activity; kind of like an athlete "bonking" or "hitting the wall" due to lack of available glycogen for the muscles; which is what is also occurring in us but in a pathological manner. This would square with the research on muscle metabolism and the demonstration that patients are "burning" ADP instead of ATP producing non-recyclable metabolic by-products that cannot be reused, stiffening the muscles, and causing problems with our ability to recover and utilize energy. We're running on glycogen due to inability to use aerobic energy sources and when that glycogen runs out it causes problems in our muscles and for our overall metabolic physiology. No wonder we hurt and are exhausted.)

Furthermore, since I have been on opiate pain medications, my sleep, cognitive symptoms, and the hyperalgesic component of the pain have mostly normalized, but I still have all of the systemic symptoms (fatigue, inability to recover, muscle pain and stiffness, mild cognitive symptoms-about the level one would would expect with a serious systemic and heart related illness, etc.) Instead of working in the typical "narcotic" manner, it doesn't seem to "put" me to sleep, rather it "allows" me to sleep when I get sleepy tired and wakes me up when I'm tired but shouldn't be "sleepy tired" (i.e., early in the day.) The paradoxical reaction can only be explained by this hypothesis in which the ingestion of opiate pain medications is acting as a form of "endorphin replacement therapy" in those for whom they are helpful. By antagonizing the micro-seizure, it appears to stop the alpha/delta wave sleep anomaly from occurring and appears to mediate the cognitive complex. It seems to normalize CNS function without any hint of the typical narcotic, psychoactive effect that people with a normal physiology experience.

In essence, the CNS dysfunction appears to be mostly secondary (at least in whatever subset I belong to since I am basing much of this on my experiences; it is very, very likely that there are subsets with a more direct brain infection and other etiological categories) since it is possible to mediate almost all of the CNS related symptoms and dysfunction through the use of various NMDA/glutamate antagonizing medications and still remain very sick and disabled.

I'd also like to point out that there are those who are sensitive to opiates just like with other medications. My guess is that these folks belong to another causal subset and/or there is enough individual variation in physiology that some patients have other biochemical pathways being affected that result in the same excitotoxic symptom complex; which would make sense as there does appear to be a number of ways that excitotoxic damage can occur. It may be that the "pure pain" fibromyalgia patients (probably a different etiological subset or more likely, subsets) are less likely to respond to opiates and may have better luck with other NMDA antagonists or GABA agonists since they may have a more "pure" excitotoxic dysfunction without the systemic, cardiac related issues (which would also explain why they do better with exercise; they likely don't have the cardiomyopathy AND retain an endorphin reaction. But this is still hypothetical.) I have also read about mechanisms in which some patients may actually develop an inability to respond to endorphin/opiates at all; how this fits into the picture, I do not know except to surmise that, again, this may be a result of subset or individual variation.

One of the things that really kills me though: If one of the primary symptoms if the lack of focus and attention, how can it be that we are "over-focused" on our symptoms? If we are not able to maintain vigilance when we are supposed to (i.e., during periods when we really SHOULD be vigilant,) how is it that we can be "hyper-vigilant." It doesn't seem logical at all.
 
...One of the things that really kills me though: If one of the primary symptoms if the lack of focus and attention, how can it be that we are "over-focused" on our symptoms? If we are not able to maintain vigilance when we are supposed to (i.e., during periods when we really SHOULD be vigilant,) how is it that we can be "hyper-vigilant." It doesn't seem logical at all.
Any psychowizard can play both sides of this game. Few such hypotheses are falsifiable.

I will offer one tiny piece of data. I have an implanted vagus nerve stimulator. Nobody is sure why sometimes this appears to work. It works for some seizure disorders, and, in a few cases, for intractable depression. When it was used on some patients with both seizures and serious depression, it sometimes relieved depression even though it had no measurable effect on seizures. After considerable thought about what on earth is going on inside me, I realized the stimulator is connected to the branch of the nerve stimulating the parasympathetic part of the autonomic nervous system. Chronic irritation of the sympathetic part of the autonomic nervous system due to infection would cause a wide range of symptoms all too familiar. Stimulating parasympathetic nerves might very well moderate these symptoms.
 
My experience with opiates which i used mainly for lower back problems, is that it helps with pain and u feel good, but it interfered with my sleep. Tramadol is good for aches and pains but need to take it in the morning, it helps with energy too. Another med i used was a slow acting morphine for my back, if i took it at night i would sleep well, i dont really know why as it didnt hype me up at all just no good for sleep(dont use anymore). I do agree with some of the other meds like benzo's and anticonsulsants(lyrica etc) as they seem to help calm the system down and i have found this helps brain fog and concentration etc as well as sleep.

cheers!!!