Implication of Epstein-Barr Virus Infection in Disease-Specific Autoreactive B Cell Activation

[deleder2k]

They will run several studies simultaneously:

- Rituximab (days 0, 14, 3 months, 6 months, 9 months and 12 months)

- FMD (flow mediated dilatation, endothelial function). FMD be measured. The purpose of this study is to measure the degree of impaired FMD and severity of the disease. You will be given nitroglycerin after measuring to measure change in FMD.
It should be examined whether FMD changes after Rituximab.
At Haukeland they also will conduct an investigation of the microcirculation of the skin on the forearm, using laser measurement.

- Irritable bowel syndrome and functional dyspepsia before and after Rituximab

- Ergo Spirometry.


They are also thinking about what they will do next. Trying the subcut version of Rituximab was mentioned.

 

[Daffodil]

we really know next to nothing about the human body do we

 

[deleder2k]

we really know next to nothing about the human body do we

Good evening, Daffo. We know a lot about the body, but not much about the immune system.

 

[Daffodil]

Good evening, Daffo. We know a lot about the body, but not much about the immune system.

if it werent for HIV, we probably would know nothing about the immune system, either!

we also seem to know nothing about the brain or gut. they throw the same meds at any mental illness one has!

 

[Hip]

Regarding the possible role of Epstein-Barr virus and HHV-6 in ME/CFS:

I should point out that it is very easy, using straightforward logic, to demonstrate that the herpes family viruses HHV-6 and EBV cannot be the triggering viruses of ME/CFS. The logic is as follows:

You can exclude these herpes family viruses from being the triggering infectious cause of ME/CFS simply by the fact that: (a) ME/CFS most frequently develops in adults; and (b) nearly all adults will already have HHV-6 and EBV in their body, since HHV-6 is usually picked up before you are 3 years old, and EBV is picked up usually in the teenage years.

Ergo, when an adult observes that they have caught some virus that then precipitates ME/CFS, it is very unlikely to be HHV-6 and EBV, since the majority of adults already have these two viruses in their bodies.

Of course, the HHV-6 and EBV already in your body could conceivably be reactivated by the immunosuppression found in ME/CFS, and may then contribute to ME/CFS symptoms; that is another story. But HHV-6 and EBV cannot be the triggering virus of ME/CFS that you catch as a adult, in the general case at least.

Enteroviruses such as coxsackievirus B and echovirus are a different story, because although one or two of these viruses may be caught early in life, there are in fact 6 serotypes of coxsackievirus B (not to mention the various sub-strains of each serotype), and there are 32 echovirus serotypes, so you can certainly catch a nasty enterovirus later in life as an adult, even if you caught one as a child.


Another issue is this: in spite of the fact that you often hear people say "ME/CFS is a condition of unknown etiology," this is not really correct, because we know that ME/CFS can be caused by parvovirus B19, Chlamydia pneumoniae, Coxiella burnetii, and Giardia lamblia. So in these cases, ME/CFS is in fact a condition of known etiology — and most of these cases of ME/CFS are pretty treatable too (except Giardia lamblia etiologies, I think).

My guess would be that most of the unknown infectious cases of ME/CFS will in fact turn out to be caused by enterovirus, which being a "stealth virus" — enterovirus hides away inside cells in its non-cytopathic form — would explain why in these unknown cases of ME/CFS, it is hard to find any evidence of infection (apart from a few herpes family virus reactivations).


Another thing to note about the the herpes family viruses HHV-6 and EBV is that they never, ever form epidemic outbreaks. Only certain species of virus are known to form epidemics, and enteroviruses are among those that do form epidemics. But HHV-6 and EBV don't. So given that ME/CFS is often observed to appear in epidemic outbreaks, again this completely rules out herpes family viruses HHV-6 and EBV as the possible viral trigger in ME/CFS epidemics.


EDIT: a new study shows that the above argument may not apply to EBV (but does still apply to HHV-6): see this post below.

 

[Valentijn]

@Hip - I think you're mostly right, especially regarding epidemics. But I think you're partially wrong regarding EBV and sporadic ME cases. Many viruses, such as Chicken Pox (also in the Herpes family), typically hit pretty hard when people get them as teens or as adults, when the same virus might have little or no effect when it hits a young child.

There's also been prospective studies regarding EBV infection, showing that X percent end up with ME/CFS. Even the psychobabblers accept it as a causative factor in some cases. But I would definitely agree that it's only causing some cases, certainly not all of them, and it would be a huge mistake to fixate on EBV as the cause of ME/CFS.

 

[Hip]

@Valentijn:

I believe you are referring to the Dubbo studies here. Certainly Dubbo indicates that EBV can lead to sporadic cases of ME/CFS. But I don't think this can be that common, because if it were were, ME/CFS would be seen as a disease that hits a lot in the teenage years, which is when most people pick up EBV.

I think this idea that partial activation/reactivation of EBV (where you don't get any viral particles made) could be driving ME/CFS is interesting. To quote this Phoenix Rising article on EBV:

"Glaser believes that the immune systems of ME/CFS patients are, in fact, largely effective at inhibiting EBV from replicating but that they are unable to shut it down early in its life cycle. In this scenario EBV is active but not producing viruses (virions); instead it’s producing proteins that trigger an immune response which is causing the symptoms in the disease.

Glaser argues that since the traditional antibody tests measure antibodies produced to antigens produced later in the infection that while they may catch signs of viral replication they miss signs of early EBV activation.

Glaser believes that cytokines (IL-1, IL-6, TNF-a) produced in reaction to these early proteins cause the ‘sickness behavior’ (i.e. lethargy, fatigue, etc.) we call ‘CFS’. "

So partial reactivation of EBV might be playing a role in some subsets of ME/CFS.

 

[snowathlete]

The logic above also discounts situations where a herpes infection could trigger a long term imbalance, culminating in ME/CFS. I had mono very badly as a teen, but eventually got over it in the most part but never felt right after that and spent a decade with health then declining and eventually being so ill I got the ME diagnosis. Is herpes to blame? Perhaps. Don't know, not necessarily. But it could result in biological systems going out of normal parameters and over time those systems become more and more dysfunctional. You could apply this to many different potential triggers in fact and it doesn't require the pathogens to be recent or to even stick around. It's not a model I favour really but I don't think the idea's been disproven and ruled out yet.

 

[Esther12]

I guess that actimeters provide some sort of standardisation but they may not actually measure whether or not someone is well. The true 'placebo' effect, as for painkiller studies, lasts a short time but all sorts of factors may produce effects that look like 'placebo' indefinitely. A lot of what appears as a placebo effect in trials hs to do with patients trying to fulfil therapists expectations for reasons relating to interpersonal interaction. And even for an actimeter this could be a problem. For instance, a week before an assessment visit a person may start doing more exercise because they are thinking about the assessment and reporting how they are doing. A person might also do more at a stage when they were feeling they needed to get better and once they got better they might say - why bother, I'm well now, I don't really need to do that much this week. For the person who is seriously incapacitated where the actimeter is measuring the difference between being in bed all day and getting to walk around the garden it may give a useful indication of ability to exercise but I suspect that at slightly higher levels of activity it may be influenced by all sorts of irrelevances. It is often a mistake to think that something that gives you a number is more use than how someone says they feel if what you really want to know is how they feel. Most people trying to design ME trials seem to think actimeters could be useful but they also introduce complications to the analysis which may make the project unwieldy.

Maybe OT for this thread, and I'm not aware of any good evidence on this, but I'd be really surprised if actimeter results for CFS trials could be swayed nearly as easily by a desire to fulfil therapists expectations as patient reports on how they feel.

I think that most patients with a restrictive illness like CFS naturally want to make the most of the energy they have, so there's less room for people to just become more active in order to please their therapist. An intervention which encourages (for example) walking might lead to improvements in actimeter data that do not reflect real improvements in health because patients end up devoting more of their limited energy to the activity being promoted, but for a drug intervention, or a psychological intervention that does not involve the therapist actively encouraging more activity, actimeter data seems much less likely to be prone to problems with response bias.

Even for CBT that is explicitly intended to encourage patients to increase activity levels in order to reduce fatigue, trials seem to indicate the this only leads to improvements in questionnaire scores, not actimeter data.

There was a paper on CBT for post-cancer fatigue which used actimeters, by the same group who used actimeters for CBT for CFS, and they found the similar results:

http://forums.phoenixrising.me/inde...fatigue-cbt-actometers-bleijenberg-etc.24838/

There's also a new paper on an exercise intervention for 'chronic fatigue' that led to big improvements in the amount of reported leisure activity (sport), but only a small improvement in actimeter data that was not statistically significant.

No outcome measure we have at the moment is ideal (or anywhere close), but I have much more interest in non-blinded trials that lead to improvements in things like actimeter data than fatigue questionnaires.

 

[Jonathan Edwards]

Maybe OT for this thread, and I'm not ware of any good evidence on this, but I'd be really surprised if actimeter results for CFS trials could be swayed nearly as easily by a desire to fulfil therapists expectations as patient reports on how they feel...
... No outcome measure we have at the moment is ideal (or anywhere close), but I have much more interest in non-blinded trials that lead to improvements in things like actimeter data than fatigue questionnaires.

I think you're right on all of that. The UCL based group has discussed this and we need to think seriously about it. The big problem is trying to keep things simple and to go for a single primary trial endpoint for statistics reasons. Using tools like actimeters without proper training in usage etc could sink an otherwise good study. There is so much methodology to get firmed up and gone are the days when one could develop these things within a clinical department as part of the ongoing development of routine care.

 

[Hip]

@snowathlete
I am referring to the generally-observed cases of infection-tiggered ME/CFS. This is where a pathogen is caught, it causes a brief flu-like illness or some other prodrome symptoms, and then ME/CFS suddenly appears almost immediately afterwards within days or weeks (rapid onset infectious ME/CFS), or appears slowly but surely and progressively over the next year or two (slow onset infectious ME/CFS).

In these cases, my argument above suggests EBV is unlikely be the trigger, except on rare occasions.


Now, whether there might other classes of infectious etiologies, like the one you depict that takes a decade or more to manifest, that's open to speculation. But at present we only have evidence for the generally-observed infectious etiologies I just described.

 

[snowathlete]

I think you're right on all of that. The UCL based group has discussed this and we need to think seriously about it. The big problem is trying to keep things simple and to go for a single primary trial endpoint for statistics reasons. Using tools like actimeters without proper training in usage etc could sink an otherwise good study. There is so much methodology to get firmed up and gone are the days when one could develop these things within a clinical department as part of the ongoing development of routine care.

I wore some kind of actimeter for a few weeks as part if a sleep study (St. John Radcliffe) and from my point of view as a patient, it was easy. Creates one heck of a lot of data to analyse, mind you and I acknowledge your point about training required for those conducting the study. Dr Enlander is using something called FitBits ( if I recall correctly) in his studies out of mt Sinai.

 

[Hip]

Just came across a new study which may contradict my theory detailed in this above post:

Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008–2012

In terms of age of onset of ME/CFS, this study found there were two peaks in the figures: a first peak in the age group 10 to 19 years, and a second peak in the age group 30 to 39 years.

So the first peak of people coming down with ME/CFS from 10 to 19 years might involve Epstein-Barr virus as a trigger, because EBV is picked up in the teenage years.

However, my theory would still stand in its argument that HHV-6 cannot be a trigger virus for ME/CFS.

 

[Woolie]

I wasn't actually suggesting that an antibody dysregulation showing itself as high EBV titres would explain anything in itself. Just that there are other possible explanations for such high titres (in the few that have them).

But although antibody dysregulation would not obviously tie in to improvement with anti-virals, looking at Dr Montoya's 2013 J Med Virol paper, I don't think there is any inconsistency. He gives as his first suggestion for the mode of action of valganciclovir 'immunomodulation' rather than an effect on virus (which he places second). Valcyte is, I understand it, a DNA replication poison, which commonly has a major effect on human blood cells as well as virus replication. So it is likely to have an effect on dividing B cells and short term antibody production.

The study must also cast doubt on whether improvements on valcyte are more than a placebo effect. If, as the study indicates, there is no major difference in response from placebo then we have to accept that people improving on valcyte may be improving for reasons other than the drug itself. This is the standard reality of studying drug treatments. We are in the same situation with rituximab and, for that matter with CBT and GET. As far as I can see we do not yet have the sort of hard evidence for treatment effects we need to start relying on.

I also understand that even in patients that improved after valcyte antibody titres did not change. If the antibody titres were evidence of replicating virus and the drug removed replicating virus this is potentially a problem for the theory that the drug is working by removing virus. Which may be why Dr Montoya went for the other explanation first? (But it would not seem to fit with valcyte correcting a B cell dysrgulation as a cause for the high titres either.)

@Jonathan Edwards
Thanks for your all contributions on the site. I have been reading over all of them with care, and really appreciate your input. I want to ask your opinion about the viruses and antivirals (although I know you're getting a lot of questions and may not be able to answer all).

I read the recent Lerner articles, and something doesn't seem to add up to me here. His idea of "abortive EBV replication" does not seem to gel well with his promotion of antivirals as a treatment. If the full lytic replication cycle is generally not completed, then how can antivirals help? My understanding is that antivirals can only inhibit the recruitment of new cells via lytic replication. On reading the article I just assumed that perhaps its a question of incidence - so perhaps there is sufficient successful lytic replication at the same time that antivirals can still reduce viral load. But there's still something not quite right here.

The other problem I have with the viral research in general is understanding why only us PWMEs are exhibiting the symptoms we are, and not the rest of the population infected with EBV. Nancy Klimas has suggested we might carry a higher viral load, by which I think she means just more latently infected cells - e.g., B cells - than normal people? But then looking at the case studies of people with EBV-related lymphomas, the same argument could surely be made of them, and why don't they have ME?

It seems to me that any complete explanation of ME seems to have to take on board the fact that so many cases seem to have an acute viral onset in otherwise perfectly healthy people. So a prime triggering factor is a virus, but what are the sustaining factors? Does the original virus - in some kind of latent state - somehow continue to play a role? Or is the chronic form of the illness some sort of cascade of ongoing immune abnormalities somehow set into motion by a long gone - or now completely inactive - virus? A kind of "dysfucntional learning" on the part of the immune system? It seems to me to make more sense that there is still some pathogen there maintaining the pattern. But then there is the problem: why is it having this effect in us and not in others?

Sorry for the long post. Would be really interested in your thoughts here, even a one-liner.

 

[Jonathan Edwards]

@Jonathan Edwards
Sorry for the long post. Would be really interested in your thoughts here, even a one-liner.

I think the one liner is that I entirely agree. Lerner's theory does not quite add up. There is a sort of have your cake and eat it aspect to the theory of partial replication that does not look convincing.

This whole issue was the topic of my talk at the last IiME conference - the point that causation in ME is likely to be complex. I cannot yet find evidence that convinces me of chronic infection being important. Even if an acute viral infection triggers an immune disturbance (rather as chlamydia does for Reiter's) it may still be that it did not really matter what the infection was and the key 'cause' of the disease was an error in immune responsiveness.

 

[Gijs]

@Jonathan Edwards , What do you think about this idea: that the sympathetic nervous system kicks off an immune cascade that causes the symptoms. It is well known that EBV reactivated under stress. I think the ANS is the key point in ME. How do you think about this hypothese?

 

[Jonathan Edwards]

@Jonathan Edwards , What do you think about this idea: that the sympathetic nervous system kicks off an immune cascade that causes the symptoms. It is well known that EBV reactivated under stress. I think the ANS is the key point in ME. How do you think about this hypothese?

I am not sure how the sympathetic nervous system could set off an immune cascade? The sympathetic nervous system only really deals with 'do more' or 'do less' sorts of signals. It might tell the spleen to 'get on with the job' but the immune system is about much more complicated signals to do with recognising individual antigens. A mistake in such complicated signalling would not seem to have much to do with a non-specific signal to get moving.

The other thing is that we know that the immune system often signals its conclusions to the body through the autonomic nervous system. When we feel sick and sweaty with flu I assume this is the autonomic system doing what the immune system tells it. That way around makes a lot of sense - that an immune cascade kicks off the sympathetic system.

I was not aware that EBV reactivated under 'stress' unless one is talking about malnutrition or severe coexistent disease like malaria or bone marrow transplant preparation therapy.

 

[Gijs]

thanks for your reply professor Edwards, what do you think about this study can this be a breakthrough for a subgroup:

Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

Madlen Loebel equal contributor *, Kristin Strohschein equal contributor, Carolin Giannini, Uwe Koelsch, Sandra Bauer, Cornelia Doebis, Sybill Thomas, Nadine Unterwalder, Volker von Baehr, Petra Reinke, Michael Knops, Leif G. Hanitsch, Christian Meisel, Hans-Dieter Volk, Carmen Scheibenbogen

Published: January 15, 2014
DOI: 10.1371/journal.pone.0085387

 

[Jonathan Edwards]

thanks for your reply professor Edwards, what do you think about this study can this be a breakthrough for a subgroup:

Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

Madlen Loebel equal contributor *, Kristin Strohschein equal contributor, Carolin Giannini, Uwe Koelsch, Sandra Bauer, Cornelia Doebis, Sybill Thomas, Nadine Unterwalder, Volker von Baehr, Petra Reinke, Michael Knops, Leif G. Hanitsch, Christian Meisel, Hans-Dieter Volk, Carmen Scheibenbogen

Published: January 15, 2014
DOI: 10.1371/journal.pone.0085387

I think this is a very interesting study, suggesting an unusual pattern of immune response to EBV in a subgroup of ME patients. What is much more difficult to assess is what it might mean in terms of mechanism. The study is on cells from blood - which are a very small proportion of immune cells that happen to be moving from one place to another at any one time. The actual immune response is hidden away in spleen and lymph nodes. If some of the findings prove to be repeatable in other groups they could provide the holy grail of a biomarker, but we need to see if that pans out.

 

[Woolie]

Thanks so much for your input, @Jonathan Edwards. Really appreciate you taking the time. Will try and dig out that conference talk!

I think this is a very interesting study, suggesting an unusual pattern of immune response to EBV in a subgroup of ME patients. What is much more difficult to assess is what it might mean in terms of mechanism. The study is on cells from blood - which are a very small proportion of immune cells that happen to be moving from one place to another at any one time. The actual immune response is hidden away in spleen and lymph nodes. If some of the findings prove to be repeatable in other groups they could provide the holy grail of a biomarker, but we need to see if that pans out.

Thanks for posting this @Gijs! This is fascinating It really addresses some of the questions I raised above, and puts forward an account that's more consistent with the full facts than any of the previous virus-based accounts. @heapsreal , I think you will like this too.