Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?

Eeyore

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@Hip - I don't understand the mechanism, so I suppose it's possible. In general, the innate immune system is always "primed" and ready for action, whereas the adaptive immune system must "learn" to recognize and react to pathogens. In theory, the innate immune system doesn't need any kind of priming, but if there is a lot of inflammation in an area, you'll see a higher density of tissue macrophages present, so the area may become more responsive to immune stimuli.

You are correct that I do not believe in chronic viral infections playing an important role in ME.

@leokitten - If you have a deficiency of one aspect of the immune system, you can break regulatory pathways. For example, many patients with HIV develop seborrheic dermatitis, which is a kind of autoinflammatory skin condition found in about 3% of the general population (generally a benign but annoying condition, usually not too hard to control with OTC meds). I'm not sure there is complete scientific consensus, but I think the most plausible theory is that depletion of FoxP3+ CD4 tregs impairs the normal ability of the immune system to regulate itself, so autoinflammatory conditions like seb derm become more common.

The immune system is extremely complicated - many parts working independently but also regulating each other and themselves. If some of them are broken, the regulatory network breaks down, leading to improper regulation of other parts.

I would not be surprised if this is in play in ME. The system is designed to work as a whole and to self regulate, so if you see dysfunction in part of it, it's quite possible that it is resulting from deficiency somewhere else.

Also, if one part does not function well, other parts may upregulate in a compensatory fashion, yet the result may actually not be what is desired.
 

halcyon

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In mice, if we deplete CD8 suppressor t cells, we can see infections last longer, as long as 2 months or so. The cellular immune response appears to be more important in coxsackie virus infection than the humoral response.
Humoral response is critical in clearing enterovirus infections, and is likely more important than innate response.

Children or adults with absent or deficient humoral immunity illustrate an important “experiment of nature” with regard to enterovirus infections of the CNS. Unlike other viruses, which are largely contained by innate and cognate cellular immunity, enteroviruses appear to be cleared from the host by predominantly antibody-mediated mechanisms.
Source

These humorally deficient patients develop persistent enterovirus infections lasting years. 1 2
 

Hip

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@Eeyore
Immune priming occurs when an initial exposure to inflammatory cytokines and other inflammatory agents acts to sensitize immune cells, so that when a second later exposure to inflammatory agents occurs, these immune cells are now more sensitive and more reactive in this second exposure to inflammatory agents.


To give a concrete example of priming that has been observed in studies:

Macrophages that are initially exposed to IFN-γ, and then later exposed to LPS, respond to this LPS with an exaggerated production of pro-inflammatory cytokines. It is observed that the first exposure to IFN-γ primes these macrophages so that their subsequent responses become exaggerated.

This priming of macrophages seems to involve several mechanisms, including the up-regulation of expression of Toll-like receptors on the macrophages. It is speculated that the effects of priming are epigenetically encoded within the immune cells.

Priming also is observed in microglial cells. Primed microglia produce stronger inflammatory and toxic responses, and not only that, they also become more sensitive to being triggered.

So you have a dual effect in priming: immune cells produce a much stronger pro-inflammatory response, and they also become more trigger happy.



It is interesting that many patients had IBS before they developed ME/CFS from a viral infection. This was my case. I had IBS-D for 5 years before I developed ME/CFS after viral infection. There is a very high comorbidity of IBS in ME/CFS. One study found 92% of ME/CFS patients had IBS in their lifetime (compared to 18% for healthy controls).1

In IBS, you have chronically higher levels of inflammatory cytokines such as IL-1β, TNF-α and IL-6. Ref: here.


So my idea was that the inflammatory cytokines from IBS might have primed the microglia, such that when you then later contracted a viral infection, the primed microglia in the brain are too easily activated by this infection, and when they become activated, then produce too strong and too toxic a response.

In this way, when you have primed microglia, even a low level chronic viral infection that would normally cause no symptoms might lead to an exaggerated microglial response, possibly leading to ME/CFS symptoms.



I previously posted some info in microglial priming in this post.
 
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halcyon

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In this way, when you have primed microglia, even a low level chronic viral infection that would normally cause no symptoms might lead to an exaggerated microglial response, possibly leading to ME/CFS symptoms.
But again, the viral infection would be perpetuating the situation, by constantly stimulating the new, naive microglia that migrate to the brain. These primed microglia don't live forever, I don't think their existence is what would be perpetuating the situation alone.
 

Eeyore

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@Hip - I can't say for sure if that's happening, but it sounds plausible to me. I don't think it's epigenetically coded - I suspect it's more plastic than that. Macrophages can polarize differently (M1, M2 A/B/C, etc. - the naming schemes and theories are currently evolving). However, the basic concept does seem like it could fit. Of course, we'd have to actually show that it happens in ME - but I can't think of any obvious reason it shouldn't. When macrophages polarize in one direction or another, they express certain transcription factors which regulate gene expression. Macrophage polarization is much more malleable than t-helper polarization though - they frequently change based on their environments and the cells / cytokines around them.

I can think of some mechanisms that could explain ME that might include something like this - but whether they are correct I don't know. No obvious contradictions as far as I can see.

I do remember reading one study on virology of herpes viruses once, and NK cells were actually an important part of the early immune response - and those cells that were previously exposed to antigen reacted more quickly and aggressively to control infection. This was perplexing to me, as NK cells are part of the innate immune system and don't "learn" like t/b cells do. Also I believe the reaction was specific - but perhaps only partly so. i.e. They aren't reacting to a piece of a virus that is highly specific (like EBNA or something like that) but rather transcription factors are being expressed that express certain PRR's relevant to a particular type of infection. So the priming theory would fit like that. It's the first I've heard of it though, and the paper made no mention of priming. The authors didn't offer any explanation for how the nk cells reacted.

@halcyon - I am skeptical on the humoral/cellular thing halcyon. I would like to see replication in other studies and really see what they are comparing. The devil is in the details I suspect. We do know that humoral immunity does play a key role in longer term immunity to enteroviruses (this is true of many viruses) - it prevents the initial infection. It's also not surprising that people who have impaired humoral immunity would do worse in controlling any infection at all. It's not so simple as saying that cellular immunity is used for intracellular and humoral for extracellular and there is no overlap - that isn't how it works. Both arms work together effectively, and if either is disabled, control of infections will be impaired. I would suspect that those will cellular immune defects would do worse than those with humoral immune defects if the level of deficiency is comparable - and that each would do worse than a normal immune system.

The other reason i'm skeptical is that there is a lot of evidence that enteroviral infections are a common trigger in ME, and in ME, the humoral immune system is intact and functions normally - or may even be overactive. There is much more evidence for impairment of the cellular immune system - based on nk cell function, t-helper subset shifting and cytokine profiles, common trigger infections, etc. - so it seems that if it were true that the cellular were much less important than humoral, enteroviral infection would not lead to ME very often if ever.

BTW - microglia are somewhat different from other immune cells. Because they live inside the BBB, and do not cross it at all unless there is some inflammation, they are self-perpetuating. During infection, a non-microglial tissue macrophage will grow in size and prepare lysosomes, etc., but it won't divide and make more of itself. More monocytes will be recruited from the peripheral blood. Microglia, on the other hand, will divide first, and then attack. This way the population is preserved.

Caveat: Again, this is oversimplified. When there is a lot of inflammation the BBB becomes more leaky and macrophages from outside the CNS come into the brain to "assist" with the infection. There is also evidence that when you replace bone marrow, microglial cells eventually do get replaced too - although it's not clear if this only happens when there is inflammation, and how long microglia can self-replicate.
 

halcyon

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We do know that humoral immunity does play a key role in longer term immunity to enteroviruses (this is true of many viruses) - it prevents the initial infection.
Of course, this is the basis for vaccines.

It's also not surprising that people who have impaired humoral immunity would do worse in controlling any infection at all. It's not so simple as saying that cellular immunity is used for intracellular and humoral for extracellular and there is no overlap - that isn't how it works. Both arms work together effectively, and if either is disabled, control of infections will be impaired. I would suspect that those will cellular immune defects would do worse than those with humoral immune defects if the level of deficiency is comparable - and that each would do worse than a normal immune system.
As far as I understand, antibodies can't enter cells, so the humoral arm of the immune system can't directly fight intracellular infection. Your example shows that innate immunity contributes to viral clearance, but isn't crucial. My example shows that humoral immunity is crucial, and that with intact innate immunity but no humoral immunity the virus still isn't cleared.

If you want more examples, take a look in the literature for enterovirus complications during rituximab treatment. There have been a number of fatal cases.

The other reason i'm skeptical is that there is a lot of evidence that enteroviral infections are a common trigger in ME, and in ME, the humoral immune system is intact and functions normally - or may even be overactive. There is much more evidence for impairment of the cellular immune system - based on nk cell function, t-helper subset shifting and cytokine profiles, common trigger infections, etc. - so it seems that if it were true that the cellular were much less important than humoral, enteroviral infection would not lead to ME very often if ever.
Yes, but nobody has looked at these values in people before they develop ME. The shift could be occurring because of the disease, not that it's the cause of it. Despite the th2 shift, IgG subclass deficiencies have been found in ME patients and it seems likely that this condition predates the ME onset and could even contribute to it, but again without looking at people before they became ill we can't know which came first.

BTW - microglia are somewhat different from other immune cells. Because they live inside the BBB, and do not cross it at all unless there is some inflammation, they are self-perpetuating. During infection, a non-microglial tissue macrophage will grow in size and prepare lysosomes, etc., but it won't divide and make more of itself. More monocytes will be recruited from the peripheral blood. Microglia, on the other hand, will divide first, and then attack. This way the population is preserved.
You're correct, I misunderstood what I was reading previously.
 

leokitten

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At this point, with all the knowledge we have on this disease to date, I don't believe the root cause is neurobiological in nature. Anything that is happening in the brain, neuroinflammation etc, is likely a result of what is happening outside.

It has been found in other diseases with peripheral immune activation and autoimmunity that this has a secondary effect causing neuroinflammation and cerebral atrophy.

Some examples:
Structural changes of the brain in rheumatoid arthritis

Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome

Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses

Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement
 
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Hip

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At this point, with all the knowledge we have on this disease to date, I don't believe the root cause is neurobiological in nature. Anything that is happening in the brain, neuroinflammation etc, is likely a result of what is happening outside.
That is feasible to an extent, because the pathways like the vagus nerve that sense peripheral inflammation and then activate sickness behavior also activate central inflammation (ie, inflammation in the central nervous system).

The following article talks about how the pathways that activate sickness behavior also activate inflammation in the central nervous system:

The Impact of Systemic Inflammation on Brain Inflammation

The author is Professor Hugh Perry, who also one of the immune priming researchers mentioned earlier.



But although peripheral inflammation is likely playing a role in creating neuroinflammation and sickness behavior in ME/CFS, note that two separate autopsy studies on ME/CFS patients found enterovirus / coxsackievirus B in the brain tissues, and this was not found in the brains of healthy controls.

So an ongoing enterovirus infection in the brain may be playing a role in ME/CFS as well.

In fact, I wonder whether it is an enterovirus brain infection that is priming the microglia, so that they become oversensitive to input from the vagus nerve, thus leading to exaggerated neuroinflammatory responses and sickness behavior. In other words, an enterovirus brain infection could be priming the microglia, so that they respond too strongly to peripheral inflammation signals.
 

Eeyore

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@halcyon - I would challenge you to find an example of a patient lacking cellular immunity surviving any viral infection.

Antibodies don't generally enter cells - cells present antigens on their surfaces in what are called MHC class I molecules (e.g. HLA-A, HLA-B, and HLA-C).

Antibodies can bind to these proteins expressed on the surface of cells that are virally infected, which increases the likelihood the cells will be phagocytosed and killed. Antibodies are opsonins. This is part of the inter-operability of the 2 branches of the immune system. This process is known as ADCC - Antibody Dependent Cell-mediated (or Cellular) Cytotoxiciy.

So ultimately, it is crucial to have cellular immunity functional on some level to clear intracellular pathogens. Antibodies alone will not do it, but they seem to "spread the word" effectively throughout the body, increasing the efficiency of the cellular immune system.

It's generally rare to find either branch working alone, although they play different roles in different infections.
 

Hip

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The following is an interesting article on enterovirus persistence:

Enterovirus Persistence as a Mechanism in the Pathogenesis of Type 1 Diabetes - Enagnon K Alidjinou - Discovery Medicine

The article points out that non-cytolytic enterovirus infections only really occur in quiescent, non-dividing categories of cell. This includes neurons and glial cells (so that means non-cytolytic infections would be theoretically possible in Schwann cells).

You do not get any significant numbers of non-cytolytic enteroviruses produced when rapidly dividing cells (like liver cells for example) are infected with enterovirus. When rapidly diving cells are infected with enterovirus, nearly all the viruses produced in these cells will be the lytic type, and only a tiny percentage will be the non-cytolytic type.

But in quiescent cells, you get a substantial production of non-cytolytic enteroviruses.

So you only really find these chronic low level non-cytolytic enterovirus infections in the non-dividing, quiescent cells of the body.


One thing new to me in this article is the fact that enterovirus can infect the thymus gland, and it is suggested that this could be involved in the pathogenesis of autoimmunity:
CVB can infect the thymus, whose most important role is the induction of central tolerance, i.e., the ability of T cells to discriminate ’self’ from ‘non-self’. A persistent CVB infection of thymic cells could lead to the disturbance of immune tolerance and contribute to the autoimmune process in T1D, by loss of central self-tolerance to insulin-secreting pancreatic β cells (Jaïdane et al., 2012a).
 
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halcyon

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Let's approach this from another angle. Ignoring the negative pathogen studies, a number of which (including Lipkin's) are unpublished and unreplicated, what studies done on well characterized ME patients have produced results that would be incompatible with a ongoing viral cause?
 

SOC

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I wonder whether we even know what we mean by "cause" when we don't even really know what this illness is.

Suppose, for example, that the original trigger for the illness is a particular pathogen that damages the immune system, but is then completely cleared. The result for the patient is a reduced ability to fight pathogens so that over the years each patient may suffer from many different acute, chronic, and reactivated pathogens which cause a variety of symptoms, while a failing immune system maybe be causing other symptoms (autoimmune, or cytokine-based) independent of any specific pathogen. Where is the "cause" here? The original cause might be the original, brief pathogen which damaged the immune system and is therefore undetectable in the body later. But the "cause" of on-going symptoms might be the ever-changing list of pathogens -- different in different patients or even in the same patients over time, which are now a problem because of an impaired immune system. Or maybe some of the on-going symptoms are the result of a disordered or exhausted immune system. Are we talking about the original root cause of the illness, or the cause of current symptoms, which may or may not be the same thing?

There are probably a number of different scenarios in which the origin of the condition may be different from the reason behind current symptoms. We will be constantly talking at cross purposes if we are not using the same meaning of "cause" when we say "the cause of ME/CFS".
 

halcyon

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Are we talking about the original root cause of the illness, or the cause of current symptoms, which may or may not be the same thing?
When I say 'cause' I'm talking about whatever is maintaining the illness, preventing the body from going back to normal.
 

SOC

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When I say 'cause' I'm talking about whatever is maintaining the illness, preventing the body from going back to normal.
That's generally the way I think about 'cause' in ME/CFS, but then I have to admit that the cause in that sense could be different for different patients even if the origin or root of the illness is the same. In that case, we won't find a single 'cause'.
 

halcyon

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That's generally the way I think about 'cause' in ME/CFS, but then I have to admit that the cause in that sense could be different for different patients even if the origin or root of the illness is the same. In that case, we won't find a single 'cause'.
No, but it sure would be nice to nail down at least one cause.
 

ahmo

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When I say 'cause' I'm talking about whatever is maintaining the illness, preventing the body from going back to normal.
That's generally the way I think about 'cause' in ME/CFS, but then I have to admit that the cause in that sense could be different for different patients even if the origin or root of the illness is the same. In that case, we won't find a single 'cause'.
Martin Pall believes that the *cause*, once something precipitates the condition, is the vicious cycle, or rather interlocking 34 cycles, that create the NO/ONOO cycle. The quote below encapsulates his hypothesis. There are links in my sig to an excellent vid where he described it last year. For some reason, his comprehensive website is no longer available, since early this year. However the first of the Pall links in my signature is to a version of his theory, including the suggested antioxidants, on another site.

There have been a number of discussions about this through the years. And there are other takes on the issues of nitric oxide. I find he makes a compelling case, and since I finally got a bit clearer on his theory with the vid, have had a lot of success staying out of the crash zone with antioxidants. sorry about the formatting below.

These four illnesses, chronic fatigue syndrome (CFS/ME), multiple chemical sensitivity (MCS), fibromyalgia (FM) and post-traumatic stress disorder (PTSD) often occur together in the same individuals (they are comorbid) and share many symptoms in common (1,2). They also share a common pattern of case initiation: Each is often initiated (that is started) by a short-term stressor only to be followed by chronic illness that typically lasts for years and most often for life. These various similarities and overlaps among these four have led many scientists to suggest that they may share a common etiology (cause), however they have been uncertain what the cause may be. I will call these four illnesses multisystem illnesses, following the lead of some others, and will challenge here the claims they are unexplained and that even their symptoms are unexplained. What many have called the Gulf War Syndrome is a combination of all four (3; Chapter 10, ref.1).

It is my goal for this web page, to provide a detailed explanation for their overall mechanism and provide a proposed mechanism for the many symptoms and signs that they share. In web pages linked to this one, I will discuss some specific features of these illnesses and how each of these specific features may be generated by this same basic mechanism. I also provide more detailed support for the NO/ONOO- cycle mechanism outlined on this main web page, in these other web pages. My overall goal, here, is to outline the understanding of these illnesses that is documented in much greater detail in my book, ¡°Explaining ¡®Unexplained Illnesses¡¯¡± (1), as well as in many other publications (2-12).


The stressors implicated in the initiation of these illnesses are summarized in Table 1.

Table 1. Illness: Stressors Implicated in Initiation of Illness

Chronic fatigue syndrome

Viral infection, bacterial infection, organophosphorus pesticide exposure, carbon monoxide exposure, ciguatoxin poisoning, physical trauma, severe psychological stress, toxoplasmosis (protozoan) infection, ionizing radiation exposure

Multiple chemical sensitivity

Volatile organic solvent exposure, organophosphorus/carbamate pesticide exposure, organochlorine pesticide exposure, pyrethroid exposure, mercury exposure, carbon monoxide exposure, hydrogen sulfide exposure

Fibromyalgia

Physical trauma (particularly head and neck trauma), viral infection, bacterial infection, severe psychological stress, pre-existing autoimmune disease

Post-traumatic stress disorder

Severe psychological stress, physical (head) trauma

The stressors indicated in bold are the ones most commonly implicated for that specific illness. It should be noted that the majority of such stressors are implicated in the initiation of more than one illness.

The stressors indicated in bold are the ones most commonly implicated for that specific illness. It should be noted that the majority of such stressors are implicated in the initiation of more than one illness.


We have, here, 17 diverse stressors implicated in initiating these illnesses, leading one to ask, how they may do so? What I have argued, in my book (1) and elsewhere (2-10), is that each of these can act to increase nitric oxide levels. Each is reported to increase the levels of nitric oxide, or in three cases where that has not been studied, to stimulate a process which is itself known to increase nitric oxide. This is a striking common response and leads to the question about how nitric oxide increases might lead to chronic illness? My answer to that question is that nitric oxide, acting primarily through its oxidant product peroxynitrite, initiates a biochemical vicious cycle that is responsible, in turn, for the chronic illness. We have, then, an initial cause of illness (short-term stressor or stressors) acting to start this vicious cycle, with the cycle responsible for causing the chronic phase of illness. We are now calling the cycle the NO/ONOO- cycle after the structures of nitric oxide (NO) and peroxynitrite (ONOO-) but pronounced no, oh no! The cycle mechanism is outlined in Figure 1:....

upload_2015-5-27_19-15-32.png

There are five principles underlying the NO/ONOO- cycle as an explanatory model:

  • Short-term stressors that initiate cases of multisystem illnesses act by raising nitric oxide synthesis and consequent levels of nitric oxide and/or other cycle elements

  • Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite and other cycle elements is produced and maintained. This principle predicts that the various elements of the NO/ONOO- cycle will be elevated in the chronic phase of illness.

  • Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.

  • Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells, the fundamental mechanisms are local. The consequences of this primarily local mechanism show up in the multisystem illnesses through the stunning variations one sees in symptoms and signs from one patient to another. Different tissue impact of the NO/ONOO- cycle mechanism is predicted to lead to exactly such variations in symptoms and signs. One also sees evidence for this fourth principle in published brain scan studies where one can directly visualize the variable tissue distribution in the brains of patients suffering from one of these illnesses.
  • Therapy should focus on down-regulating the NO/ONOO- cycle biochemistry. In other words, we should be treating the cause, not just the symptoms.


Of these principles, we have discussed 1 and 2 above. Principle 3 predicts that the symptoms and signs of illness can be generated by elevation of one or more elements of the cycle. Some examples of how symptoms and signs of illness may be explained by the cycle are discussed below.

Principle 4 is so important that it takes up an entire chapter in my book (1). Because nitric oxide, superoxide and peroxynitrite, the three chemical compounds most central to the NO/ONOO- cycle have relatively short half lives in biological tissues, they don¡¯t diffuse very far from their site of origin in the body. Nitric oxide has the longest such half-life and it only diffuses about one millimeter from its origin or less. Furthermore, most of the mechanisms implicated by the arrows act at the cellular levels. The consequence of all of this is that the NO/ONOO- cycle may be elevated in one tissue of the body but an adjacent tissue may show little elevation and therefore have little impact by the cycle. This local nature of the cycle biochemistry means that we can have all kinds of variations in tissue impact from one patient to another, leading in turn to all kinds of variation in symptoms and signs from one individual to another. This striking variation in symptoms from one individual to another has been repeatedly been noted in these illnesses and has been one of the great puzzles about this group of illnesses. The variation can be easily explained by the local nature of the NO/ONOO- cycle mechanism.

The primarily local nature, outlined in Principle 4 does not imply that there are no systemic effects. The antioxidant depletion produced by local oxidative stress will be, to a substantial extent, systemic and some of the effects of the inflammatory cytokines are also systemic. These may, in turn, produce changes in neuroendocrine function and immune function that are also systemic. However the primary local nature helps us to understand the profound variations in symptoms and signs seen from one patient to another, how these different diseases may differ from one another and also differ from possible additional diseases that may share this NO/ONOO- cycle etiology, such as tinnitus (12).
 

SOC

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I did the Pall protocol early in my illness. It did help with my MCS symptoms and seemed to help my daughter shorter her crashes on the early days, but it didn't do anything for energy or PEM in general. So for us it was helpful, but not didn't address a cause, imo
 

Hip

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By the way, I just came across a drug called Anakinra which inhibits activation of the IL-1 receptor.

If vagus nerve-mediated sickness behavior is the cause of many ME/CFS symptoms, then this drug might conceivably ameliorate ME/CFS, because it's activation of the IL-1β receptor on the vagus nerve which triggers sickness behavior.

Anakinra (brand name Kineret) is a rheumatoid arthritis drug.



Actually.... I have just noticed that there is a clinical trial, which was set up in 2014, testing anakinra on ME/CFS patients. I can't find any info about the results; perhaps the trial has not yet started.

The downside is that this drug is very expensive; see here:
Buy Kineret Injection (Prefilled Syringe) 150 mg/ml, 0.67 ml (100 mg) syringe | 1 | £32.79 per pre-filled disposable injection

Kineret Prices and Kineret Coupons - GoodRx
 

xrunner

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In my case the Pall protocol didn't work either.
I do not believe that ME is an infectious illness. I believe it often begins with an infectious (or other) trigger but I do not believe ME is a persistent infectious state.
I'm not sure anybody knows the answer to this question.
However, if in specific cases testing says there's some sort of active infection, there's no hope of recovery until you properly treat that. But being completely cured is a different matter, it seems.
inhibits activation of the IL-1 receptor
A number of Lyme herbs can do that.