Innate Immune Changes in the Peripheral Blood

[lansbergen]

And if we simply take it that this is a subgroup marked by a particular antibody titre we have to ask what might make this relevant

As I recall it something in the patients serum reacted with an antibody Sandra used a lot in her research. Am I right or does my memory fail me?

 

[snowathlete]

I have read the paper.

Could I just say that although it does not bother me it does seem a pity (and against rules) to suggest people have closed minds about ideas without due cause. I have spent my evening reading through this paper on ME because I feel it is worthwhile to try and help PWME to tackle the problem of too little research. I do not need to do that. I am retired and have no intention of having my name on another paper. I can go back to birdwatching, painting and writing philosophy. I am being critical because I honestly think it would help PWME to be similarly critical. I can take the flack and I can feel the frustration but does it get us anywhere?

This chapter reads like a shortened version of a PhD written by the student. There are some issues that I think a supervisor or senior author really ought to have picked up and edited out but no matter. It sounds like a lot of hard work went in. The problem is I am still unclear how it hangs together.

The group chosen were studied because they had 'reactivity' to a cellular preparation that was blocked by a monoclonal antibody to a mouse virus. The text says 'Serum from these CFS patients contained reactivity, presumably an antibody' Now, as an immunologist I find it hard to know in what situation one would not know it was an antibody since reactivity would normally mean detection using an anti-human IgG. There may be a reason but as it stands this is not how I would expect this sort of data to be expressed. And that aside, it seems that there is no clear explanation for the existence of this antibody. Certainly it does not seem that it was thought that there was an infection with the mouse virus.

So we have a subgroup of ME patients with an antibody with a certain reactivity but no obvious reason for it or for thinking it has any particular significance. We also have the problem that there is no such thing as either having or not having an antibody. We all have some antibody reactivity to everything. We need to know the reasons for taking a cut off, which in this context would seem to be fairly arbitrary.

And if we simply take it that this is a subgroup marked by a particular antibody titre we have to ask what might make this relevant. ME patients can be divided up into subgroups on the basis of antibody titres to any antigen you like. It would not be a 'biomarker' unless it correlated with some 'biology' to mark - some difference from other cases. And this is where the study seems to run to ground because there are no control observations of ME patients without the antibody. So we have no reason to think the antibody is marking anything. You might say that it is interesting that various cellular and cytokine differences from normals were found. Fair enough, but we have a catch 22. These were looked for because other groups had found similar things in ME patients as a whole. Yet those findings were not consistently repeatable so this study is looking for a subset that showed more consistent changes - but without antibody-negative ME controls we do not know the results are more consistent in this subgroup - we just have another study with different results in ME that highlight the variability of findings.

And if the authors do not think the antibodies are because of a (mouse) retrovirus infection than why all the background discussion about retroviruses? I am afraid I am still looking for a biological story here. I may sound a harsh critic but the reality is that good science is really hard to do.

Thank you, Professor Edwards. We really do appreciate your taking part, even if sometimes the best of us can type without thinking first. We're not at our best I'm afraid. I just hope we give you plenty of positive remarks so that you know your partisipation is important to us.

Now, moving onto the paper. I read some of it too, though I just couldn't digest it all. I agree with you that there are some issues, which probably should have been picked up. I think as well that its trying to bite off more than it should in one go. It's trying to cover lots of different angles and probably should have been more focused, or split up into two or more papers. I suspect as well that this was the culmination of quite a broad, but detailed, training and so there is a lot being investigated.

I couldn't see what the sample sizes were. One table suggests they may be around 100 patients and 100 controls but it isn't clear that this sample was across the entire study. I found that made it hard to judge significance of what's reported. Something else I am interested in is what portion of the CFS patients were positive for this SFFV antibody? (And how many negative). It says just 3% of controls were positive, but without the other data you cant compare. Was it all of them, or much less? And do the immune findings reported in those that were positive differ from those that were negative [having read the rest of your post I see you picked up the same issue]. You would hope so, else what's the point?
So I'm pretty much concluding the same as you.

Something that we, the patients community, are probably assuming, is that you are aware of the whole XMRV history with ME/CFS? I just want to check this assumption is sound as you may have only started following ME/CFS research following the initial Rituximab report from Norway and so may have missed all the earlier fun. The history is the reason they are suspecting a retroviral element to be significant (and it seems, despite their previous negative result for XMRV they still think it is worth exploring this area for other retroviral links to the disease - which I'm neutral on).

That's interesting what you say about us all having an antibody to something. Can I ask a bit about that? My understanding - which perhaps was flawed - was that we'd only have antibodies to things we were exposed to. And therefore if you hadn't had exposure to certain things, a viral envelope in this case, then you wouldnt have antibodies against it. But are you saying that antibodies have a random element and therefore cover basically everything to some degree? Even things to which they have not yet been exposed? (presumably with the antibodies which prove useful getting replicated to larger numbers) I hope my questions make sense. I just want to understand this bit correctly.

 

[barbc56]

Please be considerate that the majority of this work was the PhD thesis work of the first author, Deborah Goetz.

I'm totally with @Ema - beggars can't be choosers, and this disease has made me a beggar!
I'm behind anyone doing any non-BPS research into the condition. I don't care how new or old they are to the field, I'm not going to write anyone off for giving something a go and not finding anything much (because they are in very good company with many researchers before them) and I expect them to make mistakes and change their minds as they progress their work. Someone looking at something unpromising now could easily go on to discover something totally different and important later on.

I have yet to read the full paper but I'll probably give it a bash in the next few days. From reading the abstract it sounds like they narrowed things down to a potential subset who all showed antibodies to a virus I am currently unfamiliar with, and then found immune dysregulation in those samples - the signficance of which is the potential that they *might* stand up to scrutiny better than previous attempts that have looked at immune markers across the whole group (i.e. not having narrowed things down to this possible subset of patients before) which have often been conflicting in their reports.

This is not about personal opinion but rather if the "research" is solid. We absolutely need stringent scientific evidence as otherwise, IMHO, it distracts from the real science of getting to the bottom of our condition. Studies that stand up to scientific critique as well as replicated are what we want.

Are we actually supposed to respect someone's ideas just because they have a PhD?

Mikoviist was not forced to backdown becase of political reasons but because the science didn't hold up. This is how science works, it's not personal. I feel that a lot of time was wasted when the xmrv fiasco could have been settled quicker. Of course hindsight is 20/20!

Is science perfect? No. Is science sometimes political and/or biased? Yes., But I can't think of a better system at this point in time. I don't think it can be said enough that science has to hold up to a standard that is beyond EBM where sometimes studies do not hold due to poor experimental design. It also has to stand up to bias and political scrutiny.

This beggar is a chooser.

Barb
ETA the word bias.

 

[Bob]

Please, let's not open up the XMRV debate! We've got three dedicated sub-forums for XMRV discussions, and many-many pages of heated arguments about XMRV. Let's move forwards.

 

[snowathlete]

I rather agree with Bob, that I don't want to waste any energy discussing the past. It has some relevant context to this new paper but besides that, I'm not keen to revisit that. I haven't been to the XMRV section of the site for a long long time.

I agree with what you're saying about solid research and replication. I think though, that its important to take account of context too, and where possible, nurture research, even if it has its limitations, or even should have been designed better, as it might lead to better research next time around. I see design problems in 99% of the studies I read, and not just ME/CFS ones. It's a huge problem in science. So you take from it what you can, you ask for better next time and you hope there is a next time if the general idea has any potential merit.

Considering the little reseach we have into our condition, do you for instance dismiss a paper which shows something potentially relevant, perhaps important, because it has small sample size so may or may not be significant?
My view, is that you should point out the sample size as a limitating factor, whilst recognizing that funding was very likely to be what compromised that element in the study. You hope that any follow up study is sufficiently funded, that that excuse is no longer tenable.

If there are other study design issues which could have been avoided, as from my reading so far, was the case here, then again it is right to highlight that and be critical of it.

The reality, is that everybody is biased and politics and personal opinion do have impacts. Some people acknowledge and work hard to reduce the influence of their bias, others seem to make no such effort at all. All I can say is that the world I live in is very grey and I work hard to keep it that way.

 

[barbc56]

It was an opinion and the first example that came to mind. It wasn't intended to spark any debate about xmrv. Perhaps it came to mind since someone mentioned Mikoviist?

Barb

 

[heapsreal]

Good to see replication of similar work done in the past. There has been a few of the cfs gurus state that the longer one is ill with cfs, the more infections they find. The study seems to back this up.

 

[heapsreal]

This study matches up well with Lipkin and Mady Hornig's findings and research.

Simmaron Research’s new immune study builds on exciting research that is changing how we think about ME/CFS.

Twenty years ago the internationally known virus hunter, Dr. Ian Lipkin of Columbia University, didn’t find Borna Virus in people with ME/CFS, but he never forgot the immune dysfunction he found. Twenty years later he found more immune dysfunction in another study.

He doesn’t know why it’s there but he does believe that all ME/CFS cases – no matter what pathogen or other factor has triggered them – devolve to a ‘common pathway’. The fact that pathogens of all types – from Epstein-Barr Virus, to SARS, to Giardia – can trigger ME/CFS suggests a core immune deficiency lies at the heart of the illness.

Every genetic study suggests an inherited susceptibility to Chronic Fatigue Syndrome is present. Dr. Mady Hornig of the Center for Infection and Immunity at Columbia University believes that a genetic predisposition in combination with an environmental trigger (such as an infection) occurring at just the right (wrong) time is probably key to coming down with ME/CFS.

For thirty or forty years you might be able to easily slough off this bug or that pathogen, but at some point for some reason the stars aligned; you were depleted in just the right way, the pathogen hit and with your immune system genetically predisposed to crack under the pressure – it did – and your entire system faltered.

http://simmaronresearch.com/2014/06/simmarons-next-immune-study-wheres-weak-link/

 

[Ernie]

Yes Lipkin and Horning must have been paying attention because this is all original serology, cytokine and Cellular Immune Changes research which includes this from 2010:

[1] Goetz, D.L.S. Cellular Immune Changes in the Peripheral Blood of Subjects Chronically Infected with XMRV. 128 (ProQuest, 2010). These data were submitted in partial fulfillment for Ph.D. requirements in October 2010 at University of Nevada-Reno

So ask why would Peterson and Ex-UNR scientist and Ex-WPI contractor Isabel Barao, PhD be given a grant for research that's already been done as seen above by Mikovits student at UNR. Where is Mikovits and her students data including all her UNR data and copies of her notebooks that have no intellectual property in them? Why are they hiding them from the taxpayers who paid for the research in them? Why are the WPI still submitting the cytokine patent every year that is Mikovits work?

 

[thegodofpleasure]

The group chosen were studied because they had 'reactivity' to a cellular preparation that was blocked by a monoclonal antibody to a mouse virus. The text says 'Serum from these CFS patients contained reactivity, presumably an antibody' Now, as an immunologist I find it hard to know in what situation one would not know it was an antibody since reactivity would normally mean detection using an anti-human IgG. There may be a reason but as it stands this is not how I would expect this sort of data to be expressed. And that aside, it seems that there is no clear explanation for the existence of this antibody. Certainly it does not seem that it was thought that there was an infection with the mouse virus.

So we have a subgroup of ME patients with an antibody with a certain reactivity but no obvious reason for it or for thinking it has any particular significance. We also have the problem that there is no such thing as either having or not having an antibody. We all have some antibody reactivity to everything. We need to know the reasons for taking a cut off, which in this context would seem to be fairly arbitrary.

The malign influence of the XMRV saga is inevitably strongly imprinted in the minds of the authors. They are consequently treading very carefully and trying to avoid making claims that they can't substantiate. One must also bear in mind that these people are currently working without any funding !

As someone who followed the XMRV story very closely, it's clear to me that the underlying message from these highly experienced retrovirologists, is that the reactivity to the experimental retrovirus SFFV, is indicative of infection with an as-yet unidentified murine retrovirus.

It is important to emphasize the difference between viruses and retroviruses - the latter being extremely tricky things to study.

Whilst one can pick holes in the detail, it's important that in so-doing, we don't ignore the bigger picture.
Perhaps the reason why they chose to publish in this way is precisely because they recognise that they can't yet answer all of the questions that would need to be addressed in a peer reviewed research paper.

 

[Kati]

Why are you trying to read it as a scientific paper, when (as you say yourself) it is to be published as a chapter in a book ?
All of the necessary information, to understand what they are proposing, is in there, if you actually read it.
Maybe recognising and accepting that they have identified an M.E/cfs sub-group, which can be defined by an easily reproducible test / biomarker would be a good starting point.

The thing is that they are trying to make it look a a scientific paper because of how they presented the abstract.

 

[Kati]

I wholeheartedly agree with all of the above.

There are groups breaking grounds. I have in mind Sonya Marshall-Gradisnik, OMI, Stanford for instance, each working in different directions. Dr Peterson's group. CFI group (the 10 million $ gift)

 

[Valentijn]

This appears to be an invited book chapter rather than a paper. For what it is worth I cannot really work out what to make of any of it (as a professor of medicine and immunology). Can anyone else understand it?

There's no scientific substance there, but politically it's very useful. And I'd rather have newbies to the ME/CFS arena reading this than the ridiculous psychological fluff about false illness beliefs, catastrophizing, and deconditioning.

While it's preferable to have solid scientific research, we also need things that have good simple titles and short conclusions which the media and general public can comprehend. Attracting very high quality researchers is not enough - the NIH still withholds funding into some of the potential biological aspects of ME/CFS when applying for funds, on the basis that some of the people reviewing the applications "believe" that ME is psychological.

For a very recent example, please refer to Ian Lipkin being turned down for funding.

So while the above article/abstract isn't the ideal thing we like to see, it's still a step in the right direction and likely to have more of a positive impact than a negative one. Hence most of us are somewhat glad to see it - It's a lot nicer than the psychosomatic alternatives which we usually get.

 

[thegodofpleasure]

The thing is that they are trying to make it look a a scientific paper because of how they presented the abstract.

Is there actually anything wrong with doing that ? IMO, their target audience will be in no doubt about what type of publication it is and why they have had to do it this way.

 

[thegodofpleasure]

There's no scientific substance there, but politically it's very useful.

I don't agree that "There's no scientific substance there" but I do accept that much of what is said isn't new science.
What is new though, is the idea that a defineable ME sub-group can be identified by an antibody test.

 

[Jonathan Edwards]

I couldn't see what the sample sizes were. One table suggests they may be around 100 patients and 100 controls but it isn't clear that this sample was across the entire study.

Something that we, the patients community, are probably assuming, is that you are aware of the whole XMRV history with ME/CFS?

That's interesting what you say about us all having an antibody to something. Can I ask a bit about that? My understanding - which perhaps was flawed - was that we'd only have antibodies to things we were exposed to. And therefore if you hadn't had exposure to certain things, a viral envelope in this case, then you wouldnt have antibodies against it. But are you saying that antibodies have a random element and therefore cover basically everything to some degree? Even things to which they have not yet been exposed?

Yes, the absence of things like sample size was another worry.

My first experience of ME research was the IiME8 conference in 2008. The first talk was by Greg Towers on XMRV. When I saw that a retrovirus was being considered in ME I was amazed, since it did not seem to add up on a system dynamic basis. I was not surprised when Greg said that he and others had identified the precise point at which sample contamination had occurred. I have subsequently read up about the XMRV story, although there will be a lot I do not know. I know that someone said that some of these people are not 'wet behind the ears'. However, most of us learn how to avoid perpetuating a mistake like that by doing more sets of blinded controls - it is not difficult. And when the blinded controls were done it turned out there was nothing there.

Yes, we all have some antibodies to everything on the planet and anything that might arrive on the planet from outer space but has not got here yet. The B cell system generates antibodies at random and there is sufficient cross talk between antibodies for all of us to show a little reactivity with everything. That reactivity may be increased a thousand fold after meeting an infection of course. So for some infections antibody levels are pretty reliable ways of indicating that you have met that infection. But for a mouse virus that as far as I know no human in infected with it is a bit hard to know what antibody levels could mean. The authors suggest some possibilities but their options indicate that they do not really understand antibody biology. They do not really answer the question.

 

[Jonathan Edwards]

This is not about personal opinion but rather if the "research" is solid.

Are we actually supposed to respect someone's ideas just because they have a PhD?

I agree Barb. But I do think Deborah Goetz may deserve some consideration on a different count - as someone who has struggled hard to get a PhD and has not been given the guidance she is entitled to hope for. Projects do not lose their way because of the student. I am aware that our discussions may add to what for her has been a tough ride.

 

[Sasha]

Could I just say that although it does not bother me it does seem a pity (and against rules) to suggest people have closed minds about ideas without due cause. I have spent my evening reading through this paper on ME because I feel it is worthwhile to try and help PWME to tackle the problem of too little research. I do not need to do that. I am retired and have no intention of having my name on another paper. I can go back to birdwatching, painting and writing philosophy. I am being critical because I honestly think it would help PWME to be similarly critical. I can take the flack and I can feel the frustration but does it get us anywhere?

There's absolutely no call for you or anybody to be subjected to any flak. None of us are anybody else's emotional punchbag here, no matter how unhappy or frustrated we get.

I hope everybody has read this:

http://forums.phoenixrising.me/index.php?threads/a-very-important-message-to-all-our-members.33031/

I'm sorry, @Jonathan Edwards. I'm sure you know how deeply, deeply grateful the vast majority of PWME are for your involvement, both in the UK rituximab trial (which may turn out to be the piece of science that finally frees us in the UK from the BPS school) and here on the forums with your engagement with us. As you say, you don't have to be here.

OK, back to the topic of the thread...

 

[Jonathan Edwards]

I agree with what you're saying about solid research and replication. I think though, that its important to take account of context too, and where possible, nurture research, even if it has its limitations, or even should have been designed better, as it might lead to better research next time around. I see design problems in 99% of the studies I read, and not just ME/CFS ones. It's a huge problem in science. So you take from it what you can, you ask for better next time and you hope there is a next time if the general idea has any potential merit.

I agree with that too. Young researchers (and by that I mean up to age 40) continually make mistakes and underestimate the methodological problems they face but they need to keep at it and be encouraged for there to be some experienced researchers in ten years time. What worried me about this paper/chapter was the fact that the broad ideas behind it did not seem to tie up. That to my mind is something that we all need to be rather ruthless at flagging up because broad ideas that do not tie up use up the majority of research funding and get perpetuated for decades and that is at least a big a problem as the limited size of funds in the first place, if not more so.

 

[Jonathan Edwards]

While it's preferable to have solid scientific research, we also need things that have good simple titles and short conclusions which the media and general public can comprehend.

I think there is some confusion about the significance of this being a 'chapter' rather than a paper. This is not intended for a general audience. It is full of technical detail and no lay person will be able to make much of it. The only difference between chapters and papers in this context is that chapters are not peer reviewed, they are invited, and they tend to be more speculative and review type. The standard of scientific rigour is no different for the different types of publication. So i am not sure where not 'reading it like a scientific paper' comes in. This piece reads as if it is an attempt to get work done for a PhD in print, not having been published in peer review papers. The primary data are referred back to the PhD itself.

So I do not think there is any reason to think that the authors are not saying they think there is a retroviral infection to avoid being turned down. The chapter will have been invited, so this is the place to say what they want to say. They should not be committing themselves to a retroviral infection because it is vanishingly unlikely that this antibody reactivity has anything to do with retroviruses in the subjects. (Unfortunately there are several places in the text that suggest that the authors do not have a very good understanding of antibody dynamics or tests, so they may not realise this.)