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Interesting study of mono/glandular fever that could be relevant to ME

Messages
3,263
I'm not quite sure what's new about this theory. It sounds pretty much like the explanation my mother gave to me when I had mono nearly fifty years ago. (At the time my mother ran the EBV research at the Central Public Health Laboratory in the UK.) Maybe things have gone around in a circle
@Jonathan Edwards, yes, it does seem to me a circle. Looks to me - from my naive point of view - that in the last decade, there has been wide acceptance of the "immune overrreactivity" hypothesis for mono/glandular fever. That is, in people who have full mono (as opposed to asymptomatic infection), there is rapid and massive expansion of the T cell pool, and this is what makes them sick. T-cell cross reactivity is often mentioned as the key mechanism here. The absence of evidence of differences in EBV loads between mono and asymtomatic carriers has been cited as support for this view.

The series of studies I recently read (not just Hadinoto, the others above too), suggest there may also be differences in EBV dynamics. So T cell crossreactivity, sure, but perhaps also a less effective response against EBV overall.

The overreactivity hypothesis on its own never did explain why mono (vs asymptomatic EBV infection) is a risk factor for Hodgkin's lymphoma.

So full circle, back to the virus itself as a key player in mono??

None of this is about MECFS directly, its about mono and EBV. But many people here who got sick after severe mono want to know why. Just saying "your immune system overreacted and is still doing so" doesn't, for many, add up to a full explanation of why they continue to be so sick when prior to mono they were perfectly healthy. The other story, "you were probably immunologically abnormal to start with, you just didn't know it till you got the mono" seems also problematic (again prior good health in many), and more importantly, difficult to falsify. What's needed is a full explanation of the mechanism which transformed these folks from healthy to chronically sick people during the course of fighting a single, very common infection. If you have one yourself, then I think people would really welcome it, because what's out there just doesn't add up.

I think the answer to this question could tell us much about MECFS with other infectious triggers, so its not just limited to those who had mono as the triggering event.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Dear Woolie,
There was a lot of discussion about plausible mechanisms, under the more general heading of ME possibly being autoimmune, in other threads maybe a year or so ago. But it is interesting to revisit this specifically in the EBV context since EBV is so unusual in its relation to B cells.

@Jonathan Edwards
The series of studies I recently read (not just Hadinoto, the others above too), suggest there may also be differences in EBV dynamics. So T cell crossreactivity, sure, but perhaps also a less effective response against EBV overall.

I was not aware that anybody had implicated T cell cross reactivity in the genesis of mono symptoms. It sounds highly implausible to me. The real difficulty here is that, unlike you Woolie, most immunologists really are sheep. They keep following each others' ideas round and round and generally can only cope with ideas that are 50 years old. My understanding is that autoreactive T cells have never been substantiated in any autoimmune or other process except for a few oddities like the AIRE thymic genetic defect and perhaps type 1 diabetes. And even where there is autoreactivity reliable evidence for cross reactivity with a foreign antigen is as far as I know not there. T cell autoreactivity due to cross reactivity never made any epidemiological sense. It was just an idea dreamt up by the early T cell enthusiasts who didn't actually know anything about patients in clinics much. If it has reared its head in EBV talk I am not surprised but hopefully it sounds as if the sheep have decided to follow something else!

@Jonathan EdwardsNone of this is about MECFS directly, its about mono and EBV. But many people here who got sick after severe mono want to know why. Just saying "your immune system overreacted and is still doing so" doesn't, for many, add up to a full explanation of why they continue to be so sick when prior to mono they were perfectly healthy. The other story, "you were probably immunologically abnormal to start with, you just didn't know it till you got the mono" seems also problematic (again prior good health in many), and more importantly, difficult to falsify. What's needed is a full explanation of the mechanism which transformed these folks from healthy to chronically sick people during the course of fighting a single, very common infection. If you have one yourself, then I think people would really welcome it, because what's out there just doesn't add up.

This is what was discussed on the threads dealing with autoimmunity. As you say 'overreacting and still doing so' is not a theory and although genetic factors are important they are only part of the answer. The main barrier to understanding is I think the repetition of the idea that causation is just genetic and environmental. If you ask an epidemiologist she will add internal stochastic to that. When Stastny provided the first evidence for genetic risk in autoimmunity he emphasised that the epidemiology indicated a major stochastic component. The same applies to ME - who gets it seems to be to a large extent random (stochastic).

That might seem strange until you realise that a random internal event followed by a perpetuating process is entirely reasonable as a basis for immune diseases. It is of course the main mechanism in cancer - a random mutation leads to a failure of control of cell growth. The immune response is interesting in that it is the one system in the body that uses a random internal mutation followed by a change in regulatory signals to do its daily work. All antibodies are initially generated at random and are produced in significant amounts if they engage a new positive feedback loop.

So the suggestion I have made previously is that there are probably several forms of ME but maybe most of them involve some random event in the immune system or maybe in the central nervous system (which also makes use of random allocations) that might be made more likely to occur during the 'cytokine storm' of a severe mono infection, which sets up a positive feedback loop either in antibody production or again maybe within neural circuits. There is probably also a T cell version, which is the chronic fatigue that comes with Reiter's syndrome, in which there seems to be a persistent shift in T cell behaviour, although there is no suggestion of autoreactivity or cross reactivity.

So when we decided to do the experiment of giving people with RA rituximab, much to the horror of most of our colleagues who believed in autoreactive T cells, we based that decision on a theory of RA with a stochastic origin based on autoantibody genesis, followed by feedback loop. The results actually turned out to be closer to what that would predict than we even expected. It looks as if the Norwegian results might point to an analogous mechanism, although probably only for some cases and it does not necessarily imply autoantibody.

To my mind the other main contender for ME would be some form of loop set up within the brain itself, not perpetuated through immune signals - rather as the Dubbo authors tend to suggest. I find this less convincing and less interesting but it may be part of the story. Moreover, even if the loop is brain based continued input from antibody mediated signals might have an effect in the long term so the two ideas may overlap.

So that's my various theories. WIthin this context EBV has the unique potential to lower the threshold for B cell mediated problems because it permanently alters survival signals for B cells. And since everyone gets it it may have an important 'permissive' role. From here on there are complexities relating to immunoglobulin Vh genes and all sorts but we need more hard data on the EBV/ME epidemiology link before I think a major investment should be put into looking for a causal connection.
 

duncan

Senior Member
Messages
2,240
I hope nobody minds if I dumb this down for a moment. Treat it like a lapse in conversational intelligence.

Fatigue is just one symptom. The reason we feel this fatigue is because our body is either fighting an infection, or thinks it is. Frequently, we have labs that demonstrate this. Many of us carry abnormal values for all sorts of pathogens: EBV, HHV-6, Coxsackie A and B and all the values therein, Lyme....I've got a long list, and I know many of us do.

So how do you select one and say it is responsible for the out-of-range values of all the others? Can we? Can I say Borrelia is causing all my other titers to go haywire? Or rather, Borrelia is responsible for impairing my immune system in such a fashion that its profile is the typical ME profile, i.e., many titers are screwed up?

The answer of course is that it might not matter...That any pathogen can act as the insult that pushes us over the edge. But THAT particular course of thought puts us on a direct trajectory with "Our faults lie not in the stars, but in ourselves." That is a convenient conclusion, but one might be hard-pressed to apply it to cluster occurrences.

Which leads us to what? Either an unknown pathogen (e.g. retroviral or undetected virus); or an autoimmune malfunction of epic proportions that can be triggered by ANY pathogen or physical trauma;or a normal immune response to a known pathogen like EBV or Lyme.

Once you get your arms around that, and make sense out of it, and embrace a choice, then what do you do with arguably the more prominent symptoms in some people? Symptoms like cognitive decline, unrelenting pain, etc? Even then you must still contend with, and explain away, the relapsing remitting nature that so often characterizes the course of ME, even to the point of daily waxes and wanes, stretched out into broader monthly or quarterly or even longer fluctuations in intensities.

There are so many variables, I swear that each time I grab hold of one, a second takes hold of me and spins me around and mocks my efforts.
 
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MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Even then you must still contend with, and explain away, the relapsing remitting nature that so often characterizes the course of ME, even to the point of daily waxes and wanes, stretched out into broader monthly or quarterly or even longer fluctuations in intensities.

There are so many variables, I swear that each time I grab hold of one, a second takes hold of me and spins me around and mocks my efforts.

There are a number of plausible theories for relapse and remission and diurnal variation.
  • Relapse often seems to happen after overexertion.
  • Some people report relapse following a (new) infection (sometimes maybe the 'infection' is actually PEM, indicating overexertion)
  • Some people report relapse following vaccination
  • Some people report relapse following chemical exposure
Re diurnal fluctuations, they could be due to:
  • Diurnal fluctuations in cortisol and/or other hormones
  • Diurnal fluctuations in cytokines (but what causes these?)
  • Diet - maybe some food intolerances
and I'm sure there are many other possibilities.
 

Research 1st

Severe ME, POTS & MCAS.
Messages
768
One thing people may have forgotten about when searching for a virus, such as EBV or a certain strain of it.....

A 'virus' doesn't need to cause ME, because the definition of a 'virus' to science, is a complete virus.

Many think of an exogenous/endogenous retrovirus or existing/novel virus and associate this to ME as a possible cause. Fine, however, this doesn't allow for a bacteria (e.g. gram negative) as the cause of ME that has genes of a virus 'inside'.

This is then important when looking at negative studies past and future. Depending on the science study performed and the language used, someone can test false negative or false positive for a virus because they certainly don't have a whole virus, but they can have a bacteria with viral genes inside. (If all you're doing is detecting viral genes).

Think back at the 'XMRV like' 'findings' that never were (not VP62/Silverman). Bacteria can or use other viral proteins DNA for it's own use. Prove this, and you have your mysterious ME retrovirus or virus (EBV hybrid) in plain sight and never need to 'find' it, because it (whole virus) isn't there in the first place.

Putting aside autoimmunity as driving the symptoms and resulting disability for a moment, the 'cause', theoretically may be neither virus or bacteria but a fusion of both into something novel.

We could have a whole virus, but a novel one hiding away in a bacteria:

For example, ''crAssphage'' (bacteriophage) was announced in 2014. A virus living inside a bacteria.
http://phenomena.nationalgeographic...eally-common-virus-only-just-been-discovered/

It's not beyond the realms of possibility that 'ME' suffers have something along this lines of this, perhaps with EBV inside Borellia/Bartonella. EBV is extremely contagious and Chronic Lyme/ME patients claim they came down with a flu like syndrome that never left them and the end up with almost identical symptoms and pathology (CFS hides the fact ME sufferers share 'Chronic Lyme' pathology and both conditions (CL and ME aren't researched).

What if a strain of EBV is floating around with viral genes in it, that cause autoimmunity? You'd never find the cause, especially with no antibodies to look for, or a weak or absent immune response due to ensuing immune suppression.
 

duncan

Senior Member
Messages
2,240
Actually, I'm pretty sure the virus hitching a ride inside Bb has been demonstrated, and if I recall it was a herpes. The whole Trojan horse thing.

I will see if I can locate that study, or the one I am most likely mistaking it for. :)

The trouble with Lyme - unlike other pathogens - is that it may in fact be the culprit behind the entire spectrum of symptoms in persistent Lyme. The jury is still out on the supposition that Bb is eradicated by conventional treatment.

But I think the virus inside a bacterium inside a...well, it's very Escher-ish, and accordingly, I like it.
 

anciendaze

Senior Member
Messages
1,841
There is plenty of room for any number of viruses inside biofilms formed by bacteria. There is already considerable literature on biofilms and known viruses. Research has not reached the point where we can feel confident all of these have been identified.

Of course bacteria can infect parasites, adding another level to your nested pictures. This is not the end of the chain. It is possible, though fairly rare, for a retrovirus to insert genes in a larger DNA virus. This happened in the case of avian reticuloendotheliosis virus (REV) and both fowlpox and Marek's disease viruses (MDV). While there were animal vaccines contaminated as a result, these were not subject to the controls on human vaccines. One point against the idea that the vaccines caused the entire problem is that it has been easier to find the complete REV genome inside MDV in fowl which have never been vaccinated.
 

msf

Senior Member
Messages
3,650
I would just like to point out that mono-like illnesses can be caused by several different organisms, and some of these can even cause a false-positive on the Monospot test. So unless those who attribute their ME to EBV had at least a positive Monospot, and preferably a positive EBV IgM result, then it seems to be jumping the gun to say that EBV is the trigger for many ME patients.

The Dubbo study did seem to suggest that this can happen, but I'm not sure whether the Dubbo study used the ICC criteria. The study also showed that Q-fever can cause chronic fatigue, so it seems that many different organisms might be able to cause something that looks like ME. I guess Prof. Edwards must also suspect this, if he sees Reactive Arthritis as part of the spectrum, but I guess it comes down to the definition of ME once again. Prof. Edwards seems to advocate categorising by the kind of immune reaction observed, but I guess it could also be categorised by the causative pathogen, or perhaps by neurological findings, as the prof suggested.
 
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3,263
Thanks for your interesting and informative reply, @Jonathan Edwards.

If you ask an epidemiologist she will add internal stochastic to that. When Stastny provided the first evidence for genetic risk in autoimmunity he emphasised that the epidemiology indicated a major stochastic component. The same applies to ME - who gets it seems to be to a large extent random (stochastic).
That might seem strange until you realise that a random internal event followed by a perpetuating process is entirely reasonable as a basis for immune diseases. It is of course the main mechanism in cancer - a random mutation leads to a failure of control of cell growth.

This idea does help me get my head around the mechanisms at play in ME, it is an interesting way of thinking about it!

In the ME literature, some recent researchers have taken the approach of using post-EBV ME as a model for studying the disease. This struck me as clever, since it overcomes some of the problems of disease heterogeneity we're faced with when studying ME. So I've been following suit in my reading too. But just hearing people on this forum talk, not everyone with the same triggering infection has the same symptoms. That is, the same trigger can lead to very different outcomes in different people. I think that's kind of the point you're making, right?

My other interest in EBV is, as you also mention, its direct involvement in the immune system (latently infected B cells). I was also much impressed by the recent epidemiological stuff showing IM to be a significant risk factor for multiple sclerosis.

To my mind the other main contender for ME would be some form of loop set up within the brain itself, not perpetuated through immune signals - rather as the Dubbo authors tend to suggest. I find this less convincing and less interesting but it may be part of the story.

I think their explanation was a super cop-out. So much careful research by this group, it really added a lot, and then what do they say ME is all down to in the end? A sort of hypersensitivity to bodily and immune sensations that people without ME would not normally find aversive. That's what I got out of that. This "theory" doesn't address any of the details regarding symtomatology - relapses, remissions, crashes, etc. - and in that way is little better than the biopsychosocial model (but maybe you've read something different?).

Thanks again for the feedback, I really feel I'm starting to get a better picture of it all.
 
Messages
3,263
So how do you select one and say it is responsible for the out-of-range values of all the others? Can we? Can I say Borrelia is causing all my other titers to go haywire? Or rather, Borrelia is responsible for impairing my immune system in such a fashion that its profile is the typical ME profile, i.e., many titers are screwed up?
Not dumned down at all, @duncan ! It is the very question bugging us all!

Once you get your arms around that, and make sense out of it, and embrace a choice, then what do you do with arguably the more prominent symptoms in some people? Symptoms like cognitive decline, unrelenting pain, etc? Even then you must still contend with, and explain away, the relapsing remitting nature that so often characterizes the course of ME, even to the point of daily waxes and wanes, stretched out into broader monthly or quarterly or even longer fluctuations in intensities.
There are so many variables, I swear that each time I grab hold of one, a second takes hold of me and spins me around and mocks my efforts.
Yes, me too. I'm not happy with any explanation that doesn't account for the fine-grained detail in our symptoms -especially relapses-remissions and high antibody titres to everything under the sun. This might not be everyone with ME, but its a huge majority.
For me, I find it easier to think about all this from some starting point, and I've chosen EBV. Cos its a known trigger infection in some cases - confirmed by the Dubbo studies - but also because it seems implicated in some other immune diseases such as MS. So we know it actually can directly modulate our immune responsiveness.
But you're right, its an arbitrary place to start!
 
Messages
3,263
The Dubbo study did seem to suggest that this can happen, but I'm not sure whether the Dubbo study used the ICC criteria. The study also showed that Q-fever can cause chronic fatigue, so it seems that many different organisms might be able to cause something that looks like ME.
I agree, @msf, it seems pretty clear to me that acute EBV infection is not the trigger in many or even most of us. I also suspect that some cases of ME triggered by EBV gradually improve over a period of years (genuine ICC ME, but relapsing-remitting then gradually improving), and for this reason, this group may have a smaller presence on forums like this. Many of us here have been sick for a long, and many are actually getting sicker, not better.

I just think EBV is a nice model - a confirmed trigger, and a known link to the immune system (via B cell infection), and a known link to at least one, if not more, immune diseases (e.g., MS). A place to start, no more and no less.
 

anciendaze

Senior Member
Messages
1,841
@anciendaze - This is something that has been of interest to me for personal reasons - can you recall any details?
The best published account was in PLoS One. (See also this article.) Contamination of fowlpox vaccine seems to have carried complete inserted retroviruses, but, as far as I know, nobody has found a complete REV provirus in MDV vaccines. This argues that the insertion event took place prior to preparation of that vaccine, because it is much easier to disable a replication-competent retrovirus than to restore function in one which is not competent. We are looking at a sequence like an insertion of complete provirus into fowlpox virus; use of this virus in preparing vaccine; infection of vaccinated fowl; spread to unvaccinated fowl, including wild fowl; insertion of provirus in MDV; accidental inclusion of defective provirus in virus used to prepare MDV vaccine.

The original recombination may well have taken place during the efforts to produce an animal model for malaria research. At that time nobody was even aware that DNA carried genetic information, so they could hardly be expected to worry about recombination. Since malaria is caused by a parasite, those researchers were not even aware they were working with a virus. If there had been a biosafety review committee, it would not even have been able to imagine this extraordinary outcome.

Evidence of viruses jumping between animals in different taxonomic classes is extremely rare.
 

Snow Leopard

Hibernating
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5,902
Location
South Australia
That might seem strange until you realise that a random internal event followed by a perpetuating process is entirely reasonable as a basis for immune diseases. It is of course the main mechanism in cancer - a random mutation leads to a failure of control of cell growth. The immune response is interesting in that it is the one system in the body that uses a random internal mutation followed by a change in regulatory signals to do its daily work. All antibodies are initially generated at random and are produced in significant amounts if they engage a new positive feedback loop.

How do germinal centre processes affect this? Yes you have an stochastic process to create variations of those antibodies, but the selection processes are not random. The outcomes of this process will be affected by any dysregulation of the immune system, including environmental (e.g. a persistent virus like EBV that actively interferes with the regulation of B cells or genetic factors (however rare). I'm not saying that there are highly specific factors (eg a patient under xyz conditions will develop an autoimmune disorder), but rather that there are still strong risk factors.

I appreciate that there is a fundamental stochastic aspect that cannot be discounted and we cannot say that the illness is entirely due to environmental/genetic factors.
 
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natasa778

Senior Member
Messages
1,774
@Jonathan Edwards : So the suggestion I have made previously is that there are probably several forms of ME but maybe most of them involve some random event in the immune system or maybe in the central nervous system (which also makes use of random allocations) that might be made more likely to occur during the 'cytokine storm' of a severe mono infection, which sets up a positive feedback loop either in antibody production or again maybe within neural circuits.


Why would such 'random' events be more likely to occur during cytokine storms?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Re Dubbo
This "theory" doesn't address any of the details regarding symtomatology - relapses, remissions, crashes, etc. - and in that way is little better than the biopsychosocial model (but maybe you've read something different?).

I agree that is a strong reason to say the Dubbo conclusion is not enough. We keep looking for evidence for immune changes in ME and it is still unclear that we have anything reliably reproducible, so I feel one cannot discount a sensitisation 'loop' within the brain as being all there is remaining long term in some people. And people with bipolar disorder presumably have brain loops and they have relapses and remissions. But ME does seem to need other factors in explanation - as you say for the pattern of crashes and some of the specific symptomatology. An ongoing fluctuating immunological drive of the sort we see in autoimmunity would fit very nicely. I guess I am just an ultra-sceptic even about the ideas I am keen on.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I would just like to point out that mono-like illnesses can be caused by several different organisms, and some of these can even cause a false-positive on the Monospot test. So unless those who attribute their ME to EBV had at least a positive Monospot, and preferably a positive EBV IgM result, then it seems to be jumping the gun to say that EBV is the trigger for many ME patients.

This is a very good point which I had forgotten about. It would be very easy to diagnose a 'mono' illness as EBV infection on the basis of IgG antibody or a wishful thinking +ve Monospot. I guess nobody looks for virus itself as a routine.

It brings me back to the fact that we may need to consider the possibility that the 'trigger' infection is not a trigger but just the firs sign of a disturbed immune system - just as infection can be a presenting feature of lupus because lupus leads to failure of control of infections.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
How do germinal centre processes affect this? Yes you have an stochastic process to create variations of those antibodies, but the selection processes are not random. The outcomes of this process will be affected by any dysregulation of the immune system, including environmental (e.g. a persistent virus like EBV that actively interferes with the regulation of B cells or genetic factors (however rare). I'm not saying that there are highly specific factors (eg a patient under xyz conditions will develop an autoimmune disorder), but rather that there are still strong risk factors.

I appreciate that there is a fundamental stochastic aspect that cannot be discounted and we cannot say that the illness is entirely due to environmental/genetic factors.

From my experience of looking at autoimmune diseases my impression is that the dysregulation that allows a positive feedback loop that should be vetoed has to be highly specific and quite different in each case. The mechanism for persistent IgG rheumatoid factor production, for instance, looks to have no cross talk with anti-topoisomerase antibody production. There are some specific cross talks in lupus and with thyroid autoantibodies more generally but otherwise the loops seem to be mutually exclusive.

You are quite right to say that once the antibody species has been generated in a new B cell that its fate in terms of mass production is tightly controlled by selection processes. Once inside the germinal centre there is of course another round of stochastic modification to the Ig gene by further mutation, which is also subject to selection pressures. If the veto process works properly then the stochastic element becomes invisible - all you see is selection. But if the veto fails probably all you say is the stochasticity. In lupus antibody production can seem to become almost totally unregulated.

Why would such 'random' events be more likely to occur during cytokine storms?

So, this is the right question, because I did not get what I said quite right. The random events are unlikely to change much. What seems more plausible is that a cytokine bath will overcome some threshold that is just about keeping the veto to anti-self in place. Allow a bit more leeway and the random event catches a loop.

But this is something my colleagues and I argued over for years because if an active immune response is underway with germinal centre expansion then the second round of random changes - the further mutations - may in fact be increased in number as compared to when we feel well. The epidemiology of most autoimmune diseases makes it lok as if infections are not really triggers but the most consistent thing about autoimmune diseases is that they are inconsistent - each one has slightly different dynamic rules.
 

A.B.

Senior Member
Messages
3,780
But ME does seem to need other factors in explanation - as you say for the pattern of crashes and some of the specific symptomatology. An ongoing fluctuating immunological drive of the sort we see in autoimmunity would fit very nicely. I guess I am just an ultra-sceptic even about the ideas I am keen on.

What do you think of the gastrointestinal symptoms that are common in ME/CFS? Do you agree that the gut is a good place to look for interesting abnormalities?