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Innate Immune Changes in the Peripheral Blood

RustyJ

Contaminated Cell Line 'RustyJ'
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1,200
Location
Mackay, Aust
(For a non CDC-aligned perspective of me/cfs, this is compulsory reading.)


NOVA Science Publishers

Innate Immune Changes in the Peripheral Blood of Chronic Fatigue Syndrome Patients: Risk Factors for Disease Progression and Management (pp. 91-130)

Authors: (Deborah L.S Goetz, Judy A. Mikovits, Jamie Deckoff-Jones, Francis W. Ruscetti, LANDRES Management Consultant, MAR Consulting Inc., Private CFS Practice, and others)

Abstract:

Chronic Fatigue Syndrome (CFS) is recognized by the WHO as an alternative name for Myalgic Encephalomyelitis, which has been classified as a disease of the central nervous system since 1969. The concept that chronic microbial infection drives constant activation of the innate immune system through alterations in the production of innate immune cells and accompanied by abnormal production of pro-inflammatory cytokines and chemokines, and that this leads to progressive immune deficiency seen in many CFS patients has only recently been appreciated. In investigating the distribution of immune cells in the peripheral blood of a cohort of CFS patients who have an antibody recognizing the SFFV envelope protein, we discovered profound alterations in the number and types of cells, particularly in the cells regulating the innate immune system.

These changes included chronic activation of monocytes and dendritic cells, and a marked increase in NKT cells and decrease in NK cells. The cytokines in plasma from these CFS patients was assayed in a multiplex platform, and one of us published findings showing signatures of infection; that is, significantly high levels of many proinflammatory mediators such as IL-12, MCP-1, IL-8, IP-10, IL-6, TNF-α, and IL-1β while being low in the critical antiviral cytokine IFN-α.

In expanding these results, we found that subsets of these CFS patients had increased TGF-β and others had increased IL-9. We will discuss these and other published results that suggest that chronic stimulation of the innate immune system is a component of the development and progression of disease in many CFS patients. In chronic diseases the resulting immunodeficiency allows activation and replication of many secondary pathogens. Thus CFS patients can share complex pathogenic complications with patients with HIV AIDS and HTLV-1 associated myelopathy.

In many CFS patient populations, the presence of several concomitant infections, from Borrelia burgdorferi to reactivated exogenous and endogenous viruses, chronically dysregulating the immune system, is a major risk factor in the development of pathology. Other risk factors include alterations in microbiota regulation, mitochondrial toxicity, cognitive dysfunction and impaired methylation pathways.

These factors can also increase the risk of others diseases, including cancer, in some CFS patients. These results have important implications for the management of many people with this diagnosis. We will review in this chapter the use of antiinflammatories, anti-virals and other therapies, as well as discussing how repurposing drugs holds promise in the treatment of patients displaying the immune abnormalities
identified in these CFS patients.

https://www.novapublishers.com/catalog/product_info.php?products_id=52282
 

thegodofpleasure

Player in a Greek Tragedy
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Before going any further, it is useful to know what SFFV's actually are and why being SFFV Ab +ve is so significant
http://www.labome.org/topics/organi...murine/spleen-focus-forming-viruses-3385.html
Summary: Strains of Murine leukemia virus (LEUKEMIA VIRUS, MURINE) that are replication-defective and rapidly transforming. The envelope gene plays an essential role in initiating erythroleukemia (LEUKEMIA, ERYTHROBLASTIC, ACUTE), manifested by splenic foci, SPLENOMEGALY, and POLYCYTHEMIA. Spleen focus-forming viruses are generated by recombination with other viral types.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
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?
 

Jonathan Edwards

"Gibberish"
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5,256
I would be grateful if you could explain what you think is being proposed thegodofpleasure. Superficially it certainly might seem to tell a coherent story but from the perspective of someone used to reading scientific documents it fails to give the basic starting information one would need to know how to make anything of it. A lot of the data are given in unconventional ways that make it very difficult to understand their significance.

I would very much like to understand what is being proposed, as I guess would many other people on the forum. Can you explain? I think if I tried I would find that I would not actually be able to formulate anything because of the gaps in starting information.
 

Snow Leopard

Hibernating
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South Australia
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?

Aim:
Measure a bunch of stuff.
Results:
A bunch of of unexpected results were found.
Discussion:
These unexpected results are very important, otherwise we wasted a lot of time measuring them (or so says our grant committee).
Conclusion:
Although we found a whole bunch of stuff, we may well be totally wrong, so a bunch of other people should also measure a bunch of stuff.

It's late so that's all I've got, sorry.
 

thegodofpleasure

Player in a Greek Tragedy
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207
Location
Matlock, Derbyshire, Uk
I would be grateful if you could explain what you think is being proposed thegodofpleasure. Superficially it certainly might seem to tell a coherent story but from the perspective of someone used to reading scientific documents it fails to give the basic starting information one would need to know how to make anything of it. A lot of the data are given in unconventional ways that make it very difficult to understand their significance.

I would very much like to understand what is being proposed, as I guess would many other people on the forum. Can you explain? I think if I tried I would find that I would not actually be able to formulate anything because of the gaps in starting information.

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.
 

Ema

Senior Member
Messages
4,729
Location
Midwest USA
Aim:
Measure a bunch of stuff.
Results:
A bunch of of unexpected results were found.
Discussion:
These unexpected results are very important, otherwise we wasted a lot of time measuring them (or so says our grant committee).
Conclusion:
Although we found a whole bunch of stuff, we may well be totally wrong, so a bunch of other people should also measure a bunch of stuff.

It's late so that's all I've got, sorry.
That seems pretty much applicable to every scientific paper, unfortunately, more or less.

I don't personally care where new ideas come from...a peer-reviewed journal, a book, the side of a bus. I think the ideas are more important than the presentation. There is plenty of time to work out which ideas are worth pursuing further and which belong in the trash bin.

I think it's short sighted to discount the content entirely because you don't care for the packaging.
 

RustyJ

Contaminated Cell Line 'RustyJ'
Messages
1,200
Location
Mackay, Aust
Full Text of the paper. Not sure everyone was aware there was one.

I don't pretend to understand much of the science here, but I'm guessing some of the confusion referred to stems from the irregularities or departures from proforma. To me it is a review of their earlier work and a statement of intent about where they are headed. I did not start the thread in the latest research forum, but in the general forum, because of its irregularities.

My, perhaps simplistic, understanding of this paper, given the personal experiences of the authors, is that it is an attempt to establish a new narrative about me/cfs, to redress the historical failing of decades of research into me/cfs, and to counter the current crop of populist CDC-aligned research groups which has recently taken to marketing and positioning themselves to attract private funding in a manner which leads to questions about whether their business is about staying in business, rather than advancing the science (with the exception of IiME).

One of the first steps towards identifying causes of ME is to identify subgroups, yet to date such efforts have been at best half-hearted, at worst, deliberately so. If there are multiple causes, then work on a theory of everything is absolutely pointless.

In investigating the distribution of immune cells in the peripheral blood of a cohort of CFS patients who have an antibody recognizing the SFFV envelope protein, we discovered profound alterations in the number and types of cells, particularly in the cells regulating the innate immune system.

Goetz and co clearly identified a significant sub group of ME - a point which has been ignored in the intervening years by the rest of the research community. Yet this is one of the most promising findings in the history of ME, if we ignore the XMRV controversies.

And rather than dropping these findings and moving onto other areas, this group is trying to progress their initial work in a practical way all the way through to drug development.

There is the strong possibility of real progress, at least with this sub cohort. There is the strong possibility of finding treatments for this cohort. While most other groups are still fumbling around in the dark.

For example, and with the greatest respect to those involved, the latest microbiome projects will not produce results to the same stage as has Goetz et al for years, if at all. At best they are exploratory projects, built around hope. Most likely they will yield information on downstream complications for patients without a clear indication of a causal agent.

The problem for Goetz/Mikovitz is to avoid talking about XMRV, but still keep retroviruses on the table. I suspect this is what has contributed to the somewhat careful language in the abstract. And I don't personally see an admission of error here. Politically Mikovitz has been forced to backdown. Perhaps this new narrative is just another way of getting her original ideas across.

Foremost though, is the desperate need for a new narrative which moves us away from the CDC, the IOM, P2P, and the dominance of the CDC-aligned research groups.

With the exception of IiME, I don't see any other group remotely coming close to opening up new frontiers in the search for a biological cause or causes. Furthermore, I don't see that these groups have the will to do so.

Research into fatigue, even the Light study which was groundbreaking, is too easily swept aside as being non-specific. Similarly, I suspect the same will happen with microbiome work. The problem is that these studies focus on symptoms not causes.
 
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snowathlete

Senior Member
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5,374
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UK
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.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
OK, so now we have some interesting suggestions about where this is coming from. I was not in fact worried about the format. A chapter format is fine but it still has to tell a scientific story. Data are no use to us unless they illustrate a well formulated biological story. It is the story here that I cannot get my head around. Superficially there seems to be a story but unless one has some anchor points that are not given it is very hard to see exactly what it can be. Maybe those anchor points are in previous papers but even in the relatively free format of a chapter the message is not going to get across to the scientific community unless it is made clear at least in general terms that they exist and how they were arrived at. It may be that the first author is underselling herself because she does not have the experience to gauge how the text will read to people outside the immediate field. In that case having input from PR members may get me to where I want to be - understanding the story.

I need to have another look in detail because I see that the order of presenting information may not be optimal and that may be half the problem.

I appreciate that people want to be supportive of this sort of research but I would like to see that support move into a new phase - a constructive critical atmosphere that raises everybody's game. I cannot make my mind up yet about this chapter but some of the ME literature is just too uncritically constructed to be any help to anyone. And I agree that that has a lot to do with commercial pressures in research.

So the key suggestion seems to be that we have a subset biomarker. Let me think about why I am cautious about that.
 

heapsreal

iherb 10% discount code OPA989,
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I guess if it doesn't fit someone's personal theories than its easier to trash talk it down.

easier to see that the immune dysfunction can leave one open to opportunistic infections, possibly a subgroup, but because auto immune theorist are tunnel visioned, they will deny infections as being an issue for cfsme.
 

thegodofpleasure

Player in a Greek Tragedy
Messages
207
Location
Matlock, Derbyshire, Uk
The problem for Goetz/Mikovitz is to avoid talking about XMRV, but still keep retroviruses on the table. I suspect this is what has contributed to the somewhat careful language in the abstract. And I don't personally see an admission of error here. Politically Mikovitz has been forced to backdown. Perhaps this new narrative is just another way of getting her original ideas across.

Foremost though, is the desperate need for a new narrative which moves us away from the CDC, the IOM, P2P, and the dominance of the CDC-aligned research groups.

With the exception of IiME, I don't see any other group remotely coming close to opening up new frontiers in the search for a biological cause or causes. Furthermore, I don't see that these groups have the will to do so.

I wholeheartedly agree with all of the above.
 

Hip

Senior Member
Messages
17,820
Politically Mikovitz has been forced to backdown

In what sense are you saying she was forced to back down politically? We know that dozens of studies were not able to replicate Mikovits's results of finding XMRV in ME/CFS patients, with contamination given as the likely reason her study found positive results. But the fact that so many replication studies were performed shows just how much the scientific community took a huge interest in her work.

Yet the groundbreaking 2007 research by Dr John Chia, which found enteroviruses in stomach tissue biopsies of 82% of ME/CFS patients, but in just 20% of controls, has inexplicably been largely ignored. Nobody has performed even one replication of Chia's stomach biopsy study, even though this is arguably the most promising new lead we have had for many years.

It seems most unjust that Mikovits had the whole world try to replicate her results, but Chia has been completely ignored.

In fact so far none of the retroviruses thought to have been found in ME/CFS patients have panned out:

Dr Sidney Grossberg — JHK retrovirus.
Dr Elaine Defreitas — HTLV-II-like retrovirus.
Dr Judy Mikovits — XMRV.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
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.