Innate Immune Changes in the Peripheral Blood

[MeSci]

Thanks, Bob. Why isn't it the abstract? Because it's in the PDF. How does one make the print blush with embarrassment?

You could use this or this.

 

[Forbin]

I'm agnostic, but I would not be too quick to rule out viruses just yet.

In his presentations, Dr. Lipkin has been careful to point out that his studies only looked at plasma and spinal fluid. At the recent Action for M.E. seminar, regarding the lack of detection HHV-6 in plasma, he said, "That's not to say that it (HHV-6) might not be present in another body site or in peripheral blood mononuclear cells which are also circulating in blood and that's something, in fact, that we need to do as part of the microbiome study."

[Whether this would also be true of some or all of the other viruses he looked at, I don't know. HIV, for instance, can become undetectable in serum even though it is "hiding" in some other tissue.]

Also, in his telephone conference earlier this year, Dr. Lipkin said, "These particular tests are not capable of detecting historical infection. The agent must be present in the plasma or the spinal fluid - in the case where we examine spinal fluid - at the time that we do that assay. Serology, which is looking for evidence of previous infections, which, I think, much of what we need to do in the future must focus, is not part of this report that I am making to you today."


One apparently non-etiological viral result that Lipkin found was that the loads of the ubiquitous anneloviruses were decreased in CFS patients. Increased loads of anneloviruses are associated with immunosuppression. Are the decreased annelovirus loads markers of immune up regulation in CFS patients? Unfortunately, this is where Dr. Lipkin's talk to Action for M.E. fades out and then fades back in...

 

[thegodofpleasure]

I think the data from Dr Mikovits's group would go in with a lot of data from other groups that has so far not yet been found to be reliably reproducible. This is the big problem we have had in making use of any testing system to select or stratify patients for a trial. We need something that gives the same answer repeatedly. The extra difficulty with using antibodies to SFFV is that the data from Dr Goetze do not even come with a control group of antibody negative CFS patients or an indication of the proportion of CFS patients with a high titre, or indeed any indication as to what should be considered a cut off titre.

So I am very interested in any test like this, indeed, if it can be shown to be reproducibly different in ME/CFS and if it correlates with immune features, but so far this test does not qualify. We also have the apparent catch22 that if this test does indeed mark a subgroup with immunodeficiency then maybe they should not be included in a rituximab study (which maybe seemed to be the message in the paper). There does not seem to be anything about the findings that would suggest that this would be a good group to treat with rituximab, which specifically targets B cell related problems.

The SFFV antibody test, which you so readily dismiss as "not yet being readily reproducible", has been proven to be exactly that, in multiple studies over a period of many years.
The SFFV Ab test identifies clear subgroups with clonal expansions of B cells, as well as those with immune deficiencies. In the context of administering Rituximab, it is obviously important to recognise the difference !
It is particularly disappointing, that in your role overseeing the UK Rituximab study, you aren't more enthusiastic to investigate this potentially useful line of enquiry.

 

[Bob]

The SFFV antibody test, which you so readily dismiss as "not yet being readily reproducible", has been proven to be exactly that, in multiple studies over a period of many years.

To be constructive, can we produce a list of papers in which SFFV antibodies have been detected in ME patients? (Or are they listed in the book article?)

 

[Bob]

We also have the apparent catch22 that if this test does indeed mark a subgroup with immunodeficiency then maybe they should not be included in a rituximab study (which maybe seemed to be the message in the paper). There does not seem to be anything about the findings that would suggest that this would be a good group to treat with rituximab, which specifically targets B cell related problems.

@Jonathan Edwards, at the top of page 101 (their page numbers) of the PDF document that we're discussing, doesn't it suggest that the presence of SFFV antibodies is related to a dysregulated immune system, (specifically in terms of uprelated CD20 & CD23 expression and mature B cell activity), rather than 'immunodeficiency' specifically?

On the same page, it also suggests that ME patients, with SFFV antibodies, would indeed be good candidates for rituximab treatment because of their B cell abnormalities. Assuming, for the sake of discussion, that their findings are correct and reproducible, it's not clear (in your previous post) why you disagree that such a subset of patients would not be suitable for rituximab. Would you mind explaining your thinking further please?

 

[Bob]

@thegodofpleasure, are you able to respond to Prof Edwards' point that ME patients without SFFV antibodies have not been used as controls so we don't know if they have the same immune dysregulation as ME patients with SFFV antibodies? In other words, how do we know that the SFFV antibodies are associated with the patterns of immune dysregulation discussed in the book article, rather than a wider cohort of ME patients having the same pattern of immune dyregulation whether or not they have the SFFV antibodies?

 

[Snow Leopard]

I don't understand all the politics but, in a nutshell, we're a bunch of very ill patients, experiencing extreme personal challenges and medical neglect, desperately clinging onto glimmers of hope. When those glimmers of hope seem to be under threat, then people (understandably) react. I think it's just a shame that we can't be slightly more pleasant and understanding towards each other, and not always jump to the worst possible conclusions before a dialogue has even begun.

I was going to write a unique reply, but its late, so... What Bob said...

 

[snowathlete]

@thegodofpleasure, are you able to respond to Prof Edwards' point that ME patients without SFFV antibodies have not been used as controls so we don't know if they have the same immune dysregulation as ME patients with SFFV antibodies? In other words, how do we know that it's the SFFV antibodies that are causing the patterns of immune dysregulation discussed in the book article?

And do we know how big this potential SFFV + subgroup is? Are we talking 10% or 70%, or what? The chapter doesn't say but perhaps previous studies give an indication?

 

[lansbergen]

And do we know how big this potential SFFV + subgroup is? Are we talking 10% or 70%, or what? The chapter doesn't say but perhaps previous studies give an indication?

From memory, about 2/3 of the samples reacted with the antibody.

 

[Hip]

Lipkin's paper has not been released to date so any definitive conclusion from it can not be substantiated. Lipkin, himself, stated that any retrovirus sequence found will not be related to CFS.

Futhermore, none of the other viruses commonly associated with ME/CFS showed up in the first pathogen screen and the high throughput screening designed to look for any viruses including novel viruses drew a blank as well.

(Bolding mine). One comment from Dr Chia on Lipkin's study:

While praising Dr. Ian Lipkin and his work, he [Chia] suggested that a study using whole blood, not just plasma, would have been more conclusive. Dr. Chia had shown this in 2005 when a study he did found enterovirus in 60% of white blood cells versus only 10% in plasma.

Source: here.

My guess is that the hunt for a specific virus or pathogen that causes ME/CFS will never be fruitful. There are certainty viruses and pathogens that are linked ME/CFS, and there are ample accounts of viral infections triggering ME/CFS (so it seems very clear that a virus can cause ME/CFS).


However, I think the important question to ask is under what circumstances can a virus precipitate ME/CFS.

ME/CFS is not like AIDS. In case of the latter, nearly everyone who catches HIV will come down with AIDS if they don't take anti-retrovirals (except a small percentage of people who have the CCR5 Delta32 mutation genetic immunity to HIV).

ME/CFS appears to be frequently triggered by respiratory viruses such as enterovirus or EBV that pass easily from person to person by normal social contact, and thus infect many other people.

Yet we know that other family members in close social contact with ME/CFS patients do not necessarily develop the disease, even though many will likely have caught the same virus. So we need to look more closely at the circumstances under which these ME/CFS-associated viruses can trigger ME/CFS, rather than assume there is a virus that always causes ME/CFS every time.

A possible clue to these circumstances comes from Dr John Chia's observation that immunosuppressive corticosteroids given during the acute phase of a viral infection seems to be a recipe for creating ME/CFS.

This observation suggests that if you take immune suppressing drugs like corticosteroids at a very critical stage when the body is trying to fight off an acute enterovirus infection, this may weaken the immune response such that the virus gets a better foothold in the body tissues — ie, the virus may penetrate deeper into the body, penetrate deeper into more tissue compartments of the body (such as the brain or nervous system) — and so this viral infection becomes chronic and permanently insinuated in the body, and the patient may then come down with ME/CFS.

What researchers also need to be doing is looking for viral infections within specific tissue compartments, not just the blood. This may require postmortem studies.

It is likely too simplistic a model to assume that there is a single pathogen responsible for triggering ME/CFS.

 

[Jonathan Edwards]

Thanks for all the queries. I could write a very long reply but actually all the issues have been covered both by me and other posters and I am not sure there is value in repeating stuff. The basic issue is that the paper we are discussing does not show that immunological findings are specific to a SFFV+ subgroup because it does not look at other subgroups. I raised this and although Dr Mikovits said that there were other publications I did not get the impression that the comparison has actually been made - she did not indicate that. So the immunological findings need to be replicated in another cohort, just as for so many such studies.

And the reality is that there is no shortage of attempts to replicate these immune measurements. Several groups have looked at all these things, including the Norwegian group, at least two UK groups, a Spanish group, Australians etc etc. The only thing that comes out obviously from these studies is that most of the time most results come out normal. And the ones that come out abnormal do not come out the same when tested in other groups even if there is some other sort of abnormality instead. B cell populations have been studied by at least four groups and do not replicate the slightly oddly described CD20/23 findings in this paper. It is not that nobody can be bothered to replicate I am afraid, it is that the results do not come out the same!

Reproducibility has to be the foundation of any usable science. Things like ANA or rheumatoid factor antibodies are found to correlate with clinical disease in the same way in every local city hospital lab throughout the civilised world - tens of thousands of times reproducible. Experience shows that results that do not behave like that are a waste of everybody's time. And most results in biomedical science do not repeat like that - for reasons that one can discuss endlessly.

The reality is that I AM very interested in any result like this that turns out to be reliable. But if am advising people how to spend cash raised by patients and carers I need to have a very long cool look at the likelihood that something is more promising than all the other stuff that looks much the same. If the percentage of ME patients that are SFFV+ is high then somebody should have found results a bit like this before. If it is low it is unlikely to help trial design much. That is the Catch22 here. You cannot argue both ways at once!

 

[MeSci]

However, I think the important question to ask is under what circumstances can a virus precipitate ME/CFS.

ME/CFS is not like AIDS. In case of the latter, nearly everyone who catches HIV will come down with AIDS if they don't take anti-retrovirals (except a small percentage of people who have the CCR5 Delta32 mutation genetic immunity to HIV).

ME/CFS appears to be frequently triggered by respiratory viruses such as enterovirus or EBV that pass easily from person to person by normal social contact, and thus infect many other people.

Yet we know that other family members in close social contact with ME/CFS patients do not necessarily develop the disease, even though many will likely have caught the same virus. So we need to look more closely at the circumstances under which these ME/CFS-associated viruses can trigger ME/CFS, rather than assume there is a virus that always causes ME/CFS every time.

A possible clue to these circumstances comes from Dr John Chia's observation that immunosuppressive corticosteroids given during the acute phase of a viral infection seems to be a recipe for creating ME/CFS.

This observation suggests that if you take immune suppressing drugs like corticosteroids at a very critical stage when the body is trying to fight off an acute enterovirus infection, this may weaken the immune response such that the virus gets a better foothold in the body tissues — ie, the virus may penetrate deeper into the body, penetrate deeper into more tissue compartments of the body (such as the brain or nervous system) — and so this viral infection becomes chronic and permanently insinuated in the body, and the patient may then come down with ME/CFS.

Or if immune systems are suppressed by overexertion or stress, as discussed in this post of mine replying to yours in another thread.

 

[Hip]

Or if immune systems are suppressed by overexertion or stress, as discussed in this post of mine replying to yours in another thread.

Yes, if extreme stress leads to elevated cortisol and the attendant immune suppression, and one catches an ME/CFS-associated virus during that period of extreme stress, it may likewise allow the virus to insinuate itself more deeply into the body, such that even when immune strength returns, the virus is now too deeply dug in for the immune system to clear or control it.

Dr Chia uncovered this etiology of acute infections + corticosteroids = ME/CFS by careful and detailed questioning of his patients' histories just prior to them coming down with ME/CFS. Chia is stickler for taking full patient histories, as he thinks all the clues are there in the history.

This corticosteroid etiology of ME/CFS seems like a very important clue, and more research should be done on this.

 

[jimells]

Or if immune systems are suppressed by overexertion or stress, as discussed in this post of mine replying to yours in another thread.

If a person is fighting off a bacterial infection (I believe my illness started as food-borne illness) could that leave the immune system less able to deal with virus?

 

[snowathlete]

Yes, if extreme stress leads to elevated cortisol and the attendant immune suppression, and one catches an ME/CFS-associated virus during that period of extreme stress, it may likewise allow the virus to insinuate itself more deeply into the body, such that even when immune strength returns, the virus is now too deeply dug in for the immune system to clear or control it.

Dr Chia uncovered this etiology of acute infections + corticosteroids = ME/CFS by careful and detailed questioning of his patients' histories just prior to them coming down with ME/CFS. Chia is stickler for taking full patient histories, as he thinks all the clues are there in the history.

This corticosteroid etiology of ME/CFS seems like a very important clue, and more research should be done on this.

anyone know what Dr Chia is doing to try and to take his research forward?

 

[Countrygirl]

Yes, if extreme stress leads to elevated cortisol and the attendant immune suppression, and one catches an ME/CFS-associated virus during that period of extreme stress, it may likewise allow the virus to insinuate itself more deeply into the body, such that even when immune strength returns, the virus is now too deeply dug in for the immune system to clear or control it.

Dr Chia uncovered this etiology of acute infections + corticosteroids = ME/CFS by careful and detailed questioning of his patients' histories just prior to them coming down with ME/CFS. Chia is stickler for taking full patient histories, as he thinks all the clues are there in the history.

This corticosteroid etiology of ME/CFS seems like a very important clue, and more research should be done on this.

Just before I developed a severe virus that caused encephalitis after which I was never the same I had received a tetanus vaccination. I read that this vaccine in particular creates an immune suppression for some considerable time. One article stated the immune system remained flying at half--mast for as long as eighteen months after vaccination.

 

[Hip]

Just before I developed a severe virus that caused encephalitis after which I was never the same I had received a tetanus vaccination. I read that this vaccine in particular creates an immune suppression for some considerable time. One article stated the immune system remained flying at half--mast for as long as eighteen months after vaccination.

I know that vaccinations can sometimes precipitate ME/CFS, but I have never heard of tetanus toxoid vaccination actually weakening the immune system.

 

[MeSci]

I know that vaccinations can sometimes precipitate ME/CFS, but I have never heard of tetanus toxoid vaccination actually weakening the immune system.

Like @Countrygirl I had a tetanus jab around the time I consider that my ME started, although I seem to have already had symptoms like leg weakness as I was 'trying to get fit' by cycling when I was attacked by a farm dog. That bite will have contained a lot of pathogens other than (possibly) tetanus.

 

[lansbergen]

That bite will have contained a lot of pathogens other than (possibly) tetanus.

People seem to forget to think about that

 

[Hip]

anyone know what Dr Chia is doing to try and to take his research forward?

Dr Chia says that:

"I tell every doctor now, you don't give steroids unless the patient's life depends on it."

But I am not aware of any research that has been funded on investigating this acute infections + corticosteroids trigger for ME/CFS.

If corticosteroids given during an acute infection can trigger ME/CFS as often as Chia indicates, there really needs to be a change in guidelines issued to all doctors, regarding curtailing the prescription of corticosteroids unless really necessary.