A neuro-immune model of ME/CFS.

[Mula]

Mula, I really appreciate all your patient work on this thread, and I also understand some of alex's objections and his desire for the model to explain more. The difficulty for yet others like myself is that we want to do two things when we read these discussions. Ultimately, of course we want to find a cure, which may take years, but in the meantime we want to understand how to improve our condition right now. So when a model is presented here that as you suggest is not for lay people, what we need is an interpreter. Clearly, this is a lot of work for such a person, but I think that is what we are missing here. What do you think? Regards, Lynne B

Appreciated Lynne. The model is a map of the whole disease. It includes all symptoms and abnormalities which have been reported and has achieved a unified mechanistic chain of reactions that could create MECFS. Various unexplored avenues of research have been opened for potential treatments through the application of this model. The interpreters will be other scientists. The treatments this model would support will need carefully conducted clinical trials. Whereas psychosomatic rehabilitation will not be applicable. If the model is correct determining treatments without clinical trials could be very harmful to patients considering the various interactions invoked by MECFS within the body.

 

[barbc56]

On a more serious note, his site, unlike most others does at least have a very credible account of what M.E/CFS is and some discussion of ther latest research - what is the 'new human enzyme' recently discovered in CFS patients but not healthy controls?
Justy.

This is a great example of pseudoscience. There are just enough scientific terms or even correct scienctific information included in the article to make it look credible. For all we know, the author of the alien abduction website could have made up the enzyme study. I don't think the author cited any credible journal articles or studies. I do believe that he really thinks his theory is correct.

I would definitely recommend the following site. It contains a lot of information about the difference between science and pseudoscience. Here they are talking about an example of pseudoscience in physics but these principles can be generalized It's rather lengthly but a good summary of pseudoscience.

http://www.lhup.edu/~dsimanek/pseudo/scipseud.htm

1. Pseudoscientists have deficient or superficial knowledge and understanding of well-established science.
   
2. Their proposals are therefore based on faulty understanding of very basic and well established principles of physics and engineering.
3. The inventors may not be at all aware of these flaws in their reasoning.
4. They feel that physics is unnecessarily complicated because physicists are 'blind' to simpler explanations.
5. Some complain that physics is "too mathematical" while others dazzle the innocent with mathematical gymnastics, mistakenly thinking that mathematics is physics, not understanding that it is only a modeling tool.
6. They obsessively focus on a narrow problem without grasping the powerful interconnectedness of physical theory. Therefore they may not be aware of the broader implications and consequences of their ideas.
7. They have inordinate confidence in themselves, plus an almost religious faith that their feelings, intuitions and hunches provide a reliable guide to scientific truth.
8. Anyone who fails to see their genius is labeled 'blind'. They love to compare themselves to innovators of the past whose ideas were initially rejected. "They laughed at Galileo, didn't they?"
9. Pseudoscientists are angry that their ideas are ignored by the scientific community. They behave as if scientists should drop whatever else it is they are doing to investigate speculative proposals, even though these proposals are not motivated by established scientific knowledge, and may be scientifically implausible.
10. Pseudoscientists have over-reliance on personal testimony of individuals, and other anecdotal evidence.
11. Pseudoscientists have an obsession with anomalous observations that seem not to fit established science theory.
12. Pseudoscientists often display an attitude of "If it feels right to me, it must be right."
13. Pseudoscientists feel that "Nothing is a coincidence."
14. Pseudoscientists have an obsession with finding "patterns" in data. Scientists must be pattern-seekers too, but it's a mistake to seek significance in patterns of things that have no possible connection or relation, such as patterns of stars in the sky (constellations), tea leaves, or ink blots.
15. Pseudoscientists often commit various abuses and misuses of statistics.
16. Pseudoscientists are motivated by considerations that lie outside the scope of science, or have already been thoroughly discredited. Example, the acupuncturists' acceptance of the reality of specific "energy pathways" in the human body. Another example: the creationists' view that science must be in harmony with their particular interpretation of the King James translation of the Bible.

Barb C.:>)

 

[jace]

I'd just like to say here, to get back to the Morris/Maes paper, that the model was pretty well complete with the work Gerwyn had done alone (with me to correct grammer, spelling, that sort of stuff). Later Maes became interested in working with Gerwyn, and acted as an editor and advisor, and added some details. For this phase, Victoria provided the secretarial services.

So, unlike the collaboration between Maes and Cort, in the Morris/Maes paper, Gerwyn was the prime mover.

 

[barbc56]

Who's Victoria. Did I miss something?
Barb C.:>)

 

[jace]

If you have access to the full paper, you will find at the end of the text, a credit for secretarial services, to me and to Victoria.

 

[alex3619]

Hi Mula, so many of the arguments you raised in post 160 are simply wrong. Wrong and incomplete papers are published all the time - just look at psychobabble. By some estimates a large percentage of published biomedical papers are wrong, even with good statistcial evidence.

I have a background in basic neuroscience, physiology and genetics as well - biochem was simply my major. Indeed I also studied anatomy and microbiology.

This model is not complete, its not parsimonious (as I already explained at length) and I am not sure what you mean by conciliatory in this context. I have checked quite a few of the references pointed to on what I considered key issues, and they are not as complete as you pretend. This I have already detailed with respect to OI. This is a good paper, but its not what you are claiming it to be.

The argument that most with the right background will get it, and those who don't will not, is deeply flawed. Few have the background to immediately understand most issues directly relating to ME and CFS, as most do not have the necessary background knowledge. A bachelor degree is like learning a language - you have the skills to read and interpret, but not necessarily all the relevant knowledge. A PhD simply means you can conduct independent research. Its not magic. Even in a narrow field nobody has all the knowledge unless the field is very very narrow, and even then I would challenge that in most cases. In the 1970s the amount of knowledge in biochemistry, for example, was doubling every four years. Nobody is up to date on all topics, but that doesn't mean that they do not have the capacity to read, analyze and intrepret papers - it just requires a little effort.

You have repeatedly stated that it explains all the symptoms. I gave you a list of things it did not explain, including one the paper itself admits was omitted. You then avoided addressing items on that list. I think that answers my question. This is a good paper. It does not completely explain all findings. It is not parsimonious. I do not know what you mean by conciliatory in this context, so I cannot address that claim.

I have made my points and people can read and make up their own minds. I do not intend to address this issue again. It is a relative minor matter.

Bye, Alex

 

[alex3619]

I wasn't aware that it is necessary to have any specific qualifications, or any association with an academic body, in order to have a paper published. I thought that it was just a case of getting the work past peer-review. Was I wrong in thinking that?

Hi Bob, some people without degrees get published if the work is of sufficient quality and relevance. Similarly no specific level of degree is necessary. Its more likely though that published research comes from those with PhDs, then Masters, etc, than those without degrees. They have the background to more easily meet the requirements, and just as importantly better access to funds. Many specific positions within organizations require a relevant PhD however, or Masters or whatever. So those who are affiated with major research institutions tend to have these qualifications.

There are quite a lot of MDs, for example, who publsh.There are quite a few independent researchers with no organizational affiliations who publish too.

Bye, Alex

 

[JT1024]

A guy I follow on twitter (known as ePatient Dave) tweeted this quote:

there is an old saying in China- “久病成良医”,​

which means prolonged illness makes the patient a good doctor. ​

​

​

He found a treatment for his stage 4 renal carcinoma online and is alive and well today preaching the importance of patient engagement and participatory medicine. Here is a link to his website: http://epatientdave.com/

The comment is appropriate in this case since many of us have had to become knowledgeable about our own conditions since we've learned doctors either don't have the time or interest to stay on top of everything.

Everyone has information on a piece of the puzzle and and the more we collaborate and are able to discuss without hostility, the better off we will be toward finding solutions.

Just my 2 cents!

 

[alex3619]

One of the hypothetical mechanisms in paper revolves around the p53/NFKB axis. The paper cites references that p53 increases mitochondrial energy production and glutathione levels. The inflammatory NFKB suppresses this mechanism and so will increase glycolysis over mitochondrial energy production. Cells and tissues with high NFKB will have lower p53, and this in turn with induce lower Foxp3 (a transcription factor, meaning it can regulate genetic transcription of important RNA in a T cell), which is needed for proper regulatory T cell immune suppression mechanisms.
http://www.ebioscience.com/knowledge-center/antigen/foxp3.htm

An implication of this is that prolonged and intense NFKB expression can drive a loss of immune tolerance. This probably would assist the development of autoantibodies and other autoimmune related mechanisms that has been shown in some of Maes' papers.

All of this so far is either implied or stated in the Maes paper.

Given the high lactate in the brain (consistent with elevated glycolysis or suppressed Krebs cycle) this might mean that brain inflammation is much higher than in the rest of the body, again consistent with many ideas about ME.

According to the wikipedia, which is not a very reliable source but easy to access, decreased or dysfunctional Tregs are associated with lupus, and an improvement in Tregs can benefit diseases including diabetes, MS, asthma and inflammatory bowel disease.
http://en.wikipedia.org/wiki/FOXP3

http://www.ugr.es/~inmuno/Novedades/ego/papersCox/day3/foxp3.pdf
"These T cells, identified by their expression of CD4, the IL-2Rα chain (CD25), and the forkhead family transcription factor Foxp3, are know as regulatory T cells, or Tregs." [my bolding]

One of the older observations in CFS (probably ME) research is an elevation of sIL2r (soluble interleukin-2 receptor). This is a Treg marker. SIL2r used to be considered a generic marker for autoimmune issues though I think the opinion may have shifted on this, I am out of date. Many CFS (probably ME) patients have this marker.

My question is this: is it possible that regulatory T cells are shedding their sIL2r, or that they are dying, as a result of lowered Foxp3 or other mechanisms? It offers the possibility that sIL2r might be a surrogate marker for Treg health?

From Zeigler: "The primary issue that has confounded these studies is that the factors that appear to affect Foxp3 expression also affect the survival and expansion of Tregs."

To counter this view though it is known that sIL2r occurs on a range of cell types, so the source might not be Tregs at all. Alternatively the shedding of sIL2r could be part of the Treg immunsuppression mechanisms (I have not researched this) and so represent an attempt by the Tregs to suppress an autoimmune problem.

In my case when I was tested in the 90s my sIL2r was thousands of times higher than it should be, but only about 25% of the theoretical maximum - theoretical because people whose sIL2r get anything like that high tend to drop dead.

The Zeigler papers also discusses lymphoproliferative disease in connection with loss of Foxp3. Is this a factor predisposing us to leukemia and lymphoma? If so then its a definite drug target, either directly or indirectly by targeting NFKB or p53. My suspicion though is an intervention aimed at modifying all three would be better.

There is a research interest in using Tregs to alter immunity, though I am wary of using retroviral vectors as discussed by Zeigler. In particular, T cells externally modified with Foxp3 can be used therapeutically to reduce contact hypersensitivity. I wonder if this is related to our skin issues or MCS? It would be interesting to find out.

The Zeigler paper is 7 years old. I am looking for better ones.

Bye, Alex

 

[Sing]

I've wondered what the connection or similarities are between ME/CFS and Lupus. From your post, Alex, it appears that a lowered Foxp3 is one specific similarity? Would you comment more on this, generally as well as specifically?

 

[alex3619]

Hi Sing, I have never investigated Foxp3 before, I am still learning. Its being used as a target for treatment for host versus graft disease amongst others. Increased Treg activity and numbers appear to decrease autoimmunity problems. Its hard for me to say more, I need to read more good and recent papers in full.

Now, purely speculative, one of the concerns I have had for a long time is localized versus whole body dysfunction. It is possible that in some parts of the body there might be very high levels of NFKB (inflammatory nuclear factor) while in others are high levels of Foxp3 which would generate a counter-action at the tissue level. I am still considering this. These are all very tissue dependent Indeed, if some cell types are out of whack one way, and others are out of whack the opposite, than any intervention to fix one (at this level) would drive the opposite type further out of whack. This is because the underlying cause (presuming for now its not completely circular) is not addressed. Correcting such a problem would take a multiple intervention strategy, carefully targeted. As I said this is speculative,Worse it appears there might be multiple such problems invovling different pathways. If so then treating ME or CFS globally will only work if it targets the cause. Now treating local hormones, paracrine and autocrine hormones (endocrine are whole body hormones) may be a way to go - which is exactly what Dr Martinovic was trying to do, as most of these are eicosanoids or twenty carbon fat hormones.

I might comment further, and at some point I might post my blog on the essential fatty acid metabolism in CFS and ME. Its way overdue but I seem to never get around to finishing it. If I discover anything more that is interesting on Foxp3 I will post a follow up comment.

Bye, Alex

 

[Guido den Broeder]

A model is an expression in formal terms (equations, logic, graphs, etc.) of someone's thoughts about certain dependencies. Its function is to help generate and check the consistency of hypotheses and expectations, and thereby to facilitate scientific discussion.

In general, models are not intended to be complete and not expected to be correct. They are a tool for the application of the scientific method, nothing more.

This one is certainly neither complete nor correct, but it is a model and as this thread shows, it serves its purpose well enough.

 

[Sing]

Excuse me, everyone, for persuing a side topic which arose from the discussion of the model. This will be brief.

Thank you, Alex. It is very tricky, isn't it?

I learned about eicosanoids from reading The Zone, years ago, and how proportions of proteins, fats and carbohydrates, amounts and timing, "control" the body's production of either "good" or "bad" eicosanoid hormones. This was revolutionary for me and I changed my diet accordingly. This is a main strategy for feeling better than otherwise. I realize from what you have written that Dr. Martinovic was also targeting the types of eicosanoids our bodies are producing, but it seems that he had a different, more extreme? dietary prescription. And then you took what you learned from this and applied it further. Is that right?

Sing

 

[alex3619]

Hi Sing, I modified what I learned from Dr Martinovic. Unlike his research I lack a clinical basis for what I have done, its more theoretical and hence unproven, although I have tested it on a biased case sample of one: me. However, in deciding on strategies to treat something as complex as ME you have to start somewhere. I too tried the principles in the Zone. I also tried to educate myself on eicosanoids ... what a wake up call. The literature is dense, complicated, convoluted and constantly changing. At the time I was researching this in depth a number of new hormones were being discovered every year. Entire journals were devoted to this topic. In order for it to be more accessible to someone who is not willing to make this a full time career I realized I would have to wait until the literature was mature enough for good condensed reviews to be produced. I do not know if that is currently the case as I only spend a few hours now and again researching this topic - but if not then at some point it will be.

I understand why you used scare quotes around "good" and "bad". These are all necessary hormones, though to some extent there are alternative hormone pathways for most of them (series 2 omega 6 eicosanoids vs. series 3 omega 3 eicosanoids). When talking about local cell to cell communication, or tissue level communication, the eicosanoids are the primary hormones. Their action is short lived though, and they cannot travel any real distance. To make things more complicated, many have half lives of only seconds which makes them tricky to study. Many inflammatory processes are eicosanoid mediated for this reason - the resulting inflammation is highly localized.

In order to fully study localized inflammatory processes in ME it is likely that fresh tissue biopsies will be mandatory. Too much of the underlying chemistry simply does not show up in blood draws. In this particular case even tissue banks may not be useful - with half lives in seconds then every second counts in testing. There are reasons why the focus is often on blood - it is cheaper, has lower risk, and is well understood. Its just too limited. The only way around this is to map either the functional genetics or proteomics driving the eicosanoids. The hormones might be gone in a few eye blinks, but the proteins and genetic factors have a much longer halflife.

Bye, Alex

 

[Sing]

Alex, So we are back to the need for good reviews and models, as well as a search for the drivers of the processes and pathways taken in ME/CFS patients vs healthy controls.

As for the relationship between type of diet and the eicosanoids which are subsequently released, that we can try on ourselves, with reference to The Zone by Dr. Barry Sears. I learned, for instance, that my body can tolerate a little higher carbohydrate than this program specifies, but the program was first designed for those who were least tolerant of carbohydrates--namely, cardiac patients in Dr. Sears practice. Dr. Sears says that people vary in a range of tolerance to carbohydrates--and the tolerance has to do with what happens with the subsequent production of insulin and other hormones in response to any particular diet.

 

[Mula]

Hi Mula, so many of the arguments you raised in post 160 are simply wrong. Wrong and incomplete papers are published all the time - just look at psychobabble. By some estimates a large percentage of published biomedical papers are wrong, even with good statistcial evidence.

I have a background in basic neuroscience, physiology and genetics as well - biochem was simply my major. Indeed I also studied anatomy and microbiology.

This model is not complete, its not parsimonious (as I already explained at length) and I am not sure what you mean by conciliatory in this context. I have checked quite a few of the references pointed to on what I considered key issues, and they are not as complete as you pretend. This I have already detailed with respect to OI. This is a good paper, but its not what you are claiming it to be.

The argument that most with the right background will get it, and those who don't will not, is deeply flawed. Few have the background to immediately understand most issues directly relating to ME and CFS, as most do not have the necessary background knowledge. A bachelor degree is like learning a language - you have the skills to read and interpret, but not necessarily all the relevant knowledge. A PhD simply means you can conduct independent research. Its not magic. Even in a narrow field nobody has all the knowledge unless the field is very very narrow, and even then I would challenge that in most cases. In the 1970s the amount of knowledge in biochemistry, for example, was doubling every four years. Nobody is up to date on all topics, but that doesn't mean that they do not have the capacity to read, analyze and intrepret papers - it just requires a little effort.

You have repeatedly stated that it explains all the symptoms. I gave you a list of things it did not explain, including one the paper itself admits was omitted. You then avoided addressing items on that list. I think that answers my question. This is a good paper. It does not completely explain all findings. It is not parsimonious. I do not know what you mean by conciliatory in this context, so I cannot address that claim.

I have made my points and people can read and make up their own minds. I do not intend to address this issue again. It is a relative minor matter.

Bye, Alex

The topic is models of disease which do need to encompass all published observations and complete with research from other branches of medicine. This is not optional. You have veered onto another topic. It is very helpful that you understand the basics of some branches of medicine the paper spans but it you would need more than this to analyses the paper. To be helpful you should begin with what is meant by the term hypothesis. You don't appear to understand this term. This model does establish a complete explanation for how the symptomatology of MECFS is established and maintained. I did explain this to you and went though each of the items you had thought were not included. Your suggestion that you do not need qualifications to study the proposed model are incompatible with the ability you have displayed in following certain concepts built into the model. On many occasions you have now wrongly stated the model is not including observations that I was easily able to locate and have held in front of you.

My question is this: is it possible that regulatory T cells are shedding their sIL2r, or that they are dying, as a result of lowered Foxp3 or other mechanisms? It offers the possibility that sIL2r might be a surrogate marker for Treg health?

sIL-2R is a marker elevated in depression.

http://www.ncbi.nlm.nih.gov/pubmed/19698376
http://www.ncbi.nlm.nih.gov/pubmed/20173400

 

[Mula]

A model is an expression in formal terms (equations, logic, graphs, etc.) of someone's thoughts about certain dependencies. Its function is to help generate and check the consistency of hypotheses and expectations, and thereby to facilitate scientific discussion. In general, models are not intended to be complete and not expected to be correct. They are a tool for the application of the scientific method, nothing more. This one is certainly neither complete nor correct, but it is a model and as this thread shows, it serves its purpose well enough.

This is an explanatory model of disease. It is a hypothesis that maps all observations into a consistent whole to foster research into areas not previous considered. Specifically they must be complete. Do not confuse complete with correct. This is a hypothetically explanation for the complete disease. If you would indicate what you have not located within the manuscript I will direct you to the correct section, but you should know this is not for lay persons.

 

[alex3619]

In reply to post 176 ... and primary depression is probably an autoimmune disease, ergo elevated sIL2r fits. The rest of the post is not worth replying to.

 

[Mula]

sIL-2R is also elevated in asthma and allergies.
http://www.ncbi.nlm.nih.gov/pubmed/16364155
http://www.ncbi.nlm.nih.gov/pubmed/12861853
http://www.ncbi.nlm.nih.gov/pubmed/10743164

 

[alex3619]

sIL2r used to be considered a generic marker of autoimmune disease. Its presence in ME supports the view that ME (and CFS) are autoimmune diseases or have substantive immune components. It may be a way to discriminate between autoimmune ME and non-autoimmune should such subtypes of ME exist. Its basically a way for the body to attempt to suppress an excessive immune response by binding to free IL-2. It would have been nice if it were specific for ME, but its a widely found marker, which is why I think not much was made of the 1990s research. One of the papers Mula posted on depression found a correlation between sIL2r and neopterin. The other said this: "Further analysis of patients revealed that sIL-2R was positively correlated with decreased activity and agitation".

In the last ten years there has been a lot of new research on sIL2r. I am not familiar with a lot of it.

Neopterin, which may correlate with sIL2r in depression, is associated with T cell loss in HIV. This article is interesting:

http://www.cabdirect.org/abstracts/20103031508.html;jsessionid=265E67D7A08EB557492F529A3587EF5E

Neopterin is inversely correlated with tetrahydrobiopterin, I wonder if sIL2r is correlated with it as well. According to the above article, the reason neopterin is liked as a biomarker is it is highly stable - it doesn't degrade or modify quickly. The same can probably not be said about sIL2r.

Low tetrahydrobiopterin feeds into Pall's peroxynitrite hypothesis. Its possible that if excessive neopterin is produced then tetrahydrobiopterin levels will decline and trigger the peroxynitrite pathways. Such an event would occur if large numbers of T cells were dying, and I wonder if excessive T cell activation might lead to the same thing. Severity of infection as the primary risk factor for development of CFS (and presumably ME) might link to this.

The wikipedia on inherited tetrahydrobiopterin deficiency: http://en.wikipedia.org/wiki/Tetrahydrobiopterin_deficiency

It says: "High levels of phenylalanine are present from infancy in people with untreated tetrahydrobiopterin (THB, BH4) deficiency. The resulting signs and symptoms range from mild to severe. Mild complications may include temporary low muscle tone. Severe complications include mental retardation, movement disorders, difficulty swallowing, seizures, behavioral problems, progressive problems with development, and an inability to control body temperature."

http://www.ncbi.nlm.nih.gov/pubmed/19581054
Pall points out that tetrahydrobiopterin levels might be increased by saunas. I found this intersting when I first read it as Martinovic found that short saunas with mulitple heat/cold cycles was beneficial in a subset of patients.

The phenylalanine link might also mean that those with ME should not consume aspartame or nutrasweet.

Bye, Alex