Theoretical Immunology

[Leonard]

Copied from the other thread: MS and heat, Why?

Hi,

Sounds like a definite correlation between fatigue and heat.

I've had MS diagnosed since the very early 1990s and had more trouble with heat then than I do now. Time does not equal progression as I don't struggle now but I have had big attacks (just to confuse the issue). Progression of what is the question.

Baclofen is a potassium channel blocker. By slowing the exit of potassium from the cell, Sodium entry is slowed. It is the influx of Sodium that triggers the release of calcium from the sarcoplasmic reticulum that triggers muscles to contract. If heat blocks the potassium channel then it should be positive not negative for muscle spasticity. Yet the opposite seems to be a common issue.

Why then, am I different? There oodles of proof of my MS but my path is different. Fatigue was a nightmare for me years ago but it isn't now. If there is a correlation between heat and fatigue then my response is still consistent, as is yours.

Regards

Hi Scott,

As we know, MS consist of two different mechanisms. The big flares are not the same as the progression. We know why. See e.g. the above thesis MS UNRAVELLED of 10 Aug.

I think the heat effect is particularly pronounced in patients who are progressive. Myself including. It gets worse every year.

The explanation is the ion pump that has ever more difficulty to maintain the equilibrium (of charging on the outside of the cell). If this charging runs down, fatique will be worse, motor functions will detoriate.

In my view the charging of the ion pump is maintained by the mitochondria. These are the main energy producing source in the cell. I think in nerve cells, the mitochiondria must be aligned in some way - I think this is what hundreds of millions of years of evolution has brought us. And when the charged particle inside the mitochondria is exchanged to form H2O - a very powerful electrical reaction, the Ca, K, Na ions must be dragged along the membrane on the outer side. I am an electrical engineer, and electrically, this is the only way I can see that it can work.

If the health of the mitochondria runs down, the heat effect - a natural protective mechanism of the cells that closes the gates or slows down the cells - will become more pronounced. If it gets colder, the mitochondria will work faster. And the pump charges better, and even progression may slow down.

Lots to think about. Not just for us, but also for the professionals.

Leo

[Scott1]

Hi Leo,

I guess you are saying the mitochondrial function is more impaired in progressive than in RR MS. I'm not sure what stage I am at but I think I am beating the odds. Last years attack was a monster and should have been substantially debilitating. It hasn't been cheap to do what I have done and it hasn't been easy either.
Can you explain how that charge on the outside of the mitochondria works? I didn't quite follow it. Do you mean the cell wall or the mitochondrial membrane?
The approach I have taken is take huge Q10 doses to benefit the inside of the mitochondrial membrane and a standard dose of acetyl-L-carnitine to enable the membrane to be permeable to ADP and ATP. I feel it has been a big help.

The relationship between heat tolerance and fatigue levels is interesting. To me it suggests the availability of ATP will be critical.

Regards

[Leonard]

Hi Scott,

In RR MS it is an acute blocking of mitochondria. The pump runs down fast. The immune system intervenes, the mitochondria start working again, the pump recharges.

In progressive MS, mitochondria successively fail (internal ATP mechanism is key), the charging (is really the dragging of ions on the other side of the cell wall = fats) will gradually slow down, the equilibrium of the pump will be more difficult to maintain. And sometimes you have to stop walking, to let the mitochondria recharge (the charging of) the pump.

Leo

[Scott1]

Hi Leo,

So your saying the ion channels themselves are impaired. (I could blame peroxynitrite for that!)

The way I do it is to really rev up the mitochondrial respiration by enhancing the electron transport chain function.

Under your approach there must be another factor.( which is a highly plausible thing.) I'm just waiting for some books on Nitric oxide. In particular, one by Louis Ignarro. He and two others won the 1998 Nobel prize for their work on the subject. It might be an interesting possibility.

Regards,

[Leonard]

Strictly speaking, it is not the ion channels themselves.
It is the supply of energy to the ion channels that is impaired.

[Scott1]

Hi Leo,

Then aren't we saying the same thing? If it is the availability of energy to the ion channels, which is ATP dependent, then don't we have to go back to the formation of ATP in the mitochondria. That in turn is dependent on fats and nucleic acids from the glycolysis side and the functioning of the electron transport chain on the other. Then it depends on the permeability of the membrane for ADP and ATP which is carnitine dependent. The carnitine would need a fatty acyl CoA enzyme (also ATP dependent) to become acetyl-L-carnitine.
If we don't do this step successfully then a progressive form of MS would become apparent as the cell function declines.
I am taking quite big doses of Q10 for the electron transport chain (750mg per night) and acetyl-L-carnitine so I don't have to make the stuff myself. It's seems to work for me.
Given my age, my long term diagnosis and the massive attack I had last year then I thought I was certainly heading to a progressive phase. Now I feel I am back in a remitting phase and the muscle tightness is due to a reperfusion injury which I will hopefully overcome.
Regards

[Leonard]

On the other thread on this forum titled Dysbiosis in the gut microbiota of PwMS on http://www.thisisms.com/forum/general-d ... 26916.html there is a great article reporting on a Japanese study about the relationship of Gut Microbiota, systemic and cellular immune responses, Inflammatory Bowel Disease and MS.
http://journals.plos.org/plosone/articl ... ne.0137429
http://www.msra.org.au/gut-bacteria-see ... -people-ms

There are also great interviews with David Perlmutter, everybody should see...


He mentions how everything is connected and how gut bacteria are changing the expression of your DNA... and let food be thy medicin....

From this site https://colloque4.inra.fr/inra_rowett_2 ... -materials you can download the congress materials. In Session 2, there are many abstracts on the "Interplay between the intestinal microbiota and the host".

What I have learned in the meanwhile is that genetics and epi-genetics are not as orthogonal as people have always thought. And that the microbiome controls the (epi-)genes where bacteria strains drive phenotypes.

The thesis MS UNRAVELLED on the previous page (49) already noted that a bad gut skews us toward getting sick. The above article explains why. The thesis then fills in the other bits and pieces, i.e. of what happens specifically in the case of MS if viral genes are no longer silenced.

[Leonard]

Extending the line of thinking in the previous posting, this study that I found on the other thread on this forum http://www.thisisms.com/forum/general-d ... 75-15.html confirms the role of the gut microbiome in MS and autoimmunity. Although the study is on mice and the EAE model, the findings of this study are much more fundamental than we might think at first sight. But what is potentially even more important, it shows that through manipulation of the gut microbiome, a "suppression of the progression" and a reversal of inflammation can be achieved.

http://journals.plos.org/plosone/articl ... ne.0009009

Conclusions/Significance

Our data provide evidence showing that the therapeutic effect of the chosen mixture of probiotic lactobacilli was associated with induction of transferable tolerogenic Tregs in MLNs, but also in the periphery and the CNS, mediated through an IL-10-dependent mechanism. Our findings indicate a therapeutic potential of oral administration of a combination of probiotics and provide a more complete understanding of the host-commensal interactions that contribute to beneficial effects in autoimmune diseases.

But probiotics are still/again in the news, possibly offering a strategy to treat MS. The MS Microbiome Consortium, a collaboration of researchers in California, Colorado, and New York, has presented early findings of differences in gut bacteria (people with MS treated with glatiramer acetate, untreated people, and healthy controls). According to the NMSS, research is continuing.

http://www.neurology.org/content/84/14_ ... ent/P2.205 The MS Microbiome Consortium (MSMC): an academic multi-disciplinary collaborative effort to elucidate the role of the gut microbiota in MS


The microbiome seems central in MS and autoimmunity. Differences in gut bacteria may change epigenetic control on the host cells. If epigenetic regulation of gene expression fails and viral genes are no longer silenced, we see an interaction in the viral repertoire.

As the study under the link below notes, endogenous viruses are mobile subcellular structures that span the divide between "self" and "foreign". Where (late infection with) EBV may trigger large scale HERV activation. At that point, cells change phenotype. And that is when autoimmune problems start.

I think we have come here to the culprit of MS. As the article rightly notes, it provides a new piece to the puzzle - a centre piece.

http://www.biomedcentral.com/1471-2377/13/111

[Leonard]

The thesis MS UNRAVELLED on the previous page (49) has a number of loose ends, for instance how to embed the role of the HERV in MS and on the microbiome and its gene expression. I think the synopsis below provides the glue that brings it all together.

MS UNRAVELLED

MS is a complicated confluence of genetic and environmental influences. SNP markers near a specific retroviral locus have shown an association with MS. Epidemiological findings suggest infection with Epstein-Barr virus (EBV) to predispose to MS. But also changes in life style, in particular westernization, are involved with a contribution from diet (Ω3 Ω6 fat balance, engrainisation, lack of phytonutritients) and lack of sun exposure, as well as the wide use of antibiotics, vaccination, c-section birth and lack of breast feeding. Possiby, things like hypoperfusion and weakened immunity may also play a role. Ref 1 and 2

The gut microbiome plays a central role in health and disease. The microbiome co-evolved with the genome. Human associated microorganisms are present in numbers exceeding the quantities of human cells by at least 10 fold. The microbiome directly influences health and provides an extra means of adaptive potential to different life styles. The microbiome compositional patterns associate with specific diseases and contain certain prognostic value. For several bacterial species, peak-to-trough coverage ratios (PTRs) correlate with the manifestation of specific disease. Ref 3, 4 and 5

The host ancestral genome structures its microbiome. While microbial communities are influenced by environmental factors (diet, metabolic factors, stress), there is some degree of genetic influence of the host on the microbiome configuration. In particular single nucleotide polymorphisms (SNPs) have shown an association with the microbiome configuration and susceptibility to several diseases including MS and other auto-inflammatory disorders. [higher incidence of women passing MS because they transmit their mtDNA to child vs Carter effect?] Ref 6, 7, 1 and 2

The microbiome plays a critical role in the epigenetic regulation of gene expression. The microbiome is central in MS and autoimmunity. Differences in gut bacteria may change epigenetic control on the host cells. If epigenetic regulation of gene expression fails and viral genes are no longer silenced, we see an interaction in the viral repertoire. Human endogenous retroviruses (HERVs) are mobile subcellular structures that span the divide between "self" and "foreign". Where (late infection with) EBV may trigger large scale HERV activation. Also the herpes virus and toxic substances as ε-toxin from the gut and the naso-pharynx are suspect. At that point, cells change phenotype. And that is when autoimmune problems start. Ref 1 and 8

RR and progressive MS are caused by two different underlying mechanisms. A double peak is seen in the graph of age of onset: T-cell mediation (cellular immunity) and B-cell mediated immunity (humoral immunity). In the early phase, T-cell mediation concentrates in the CNS. At the later stage, EBV immortalized B-cells cause progression including in particular in the spinal column. In the progressive phase, oxidative stress causes mitochondrial failure. After some time, the equilibrium of the ion pump can no longer be maintained and cells become electrically dormant. The thesis MS unraveled explains. Ref 9

As regards therapeutic options: Through manipulation of the microbiome, a reversal of inflammation can be achieved and progression be stopped. Ref 5 and 10


1. Endogenous retroviruses and multiple sclerosis–new pieces to the puzzle
http://www.biomedcentral.com/1471-2377/13/111
2. HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV
http://www.retrovirology.com/content/11/1/2
3. The MS Microbiome Consortium (MSMC): an academic multi-disciplinary collaborative effort to elucidate the role of the gut microbiota in MS
http://www.neurology.org/content/84/14_ ... ent/P2.205
4. The role of microbiome in central nervous system disorders
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062078/
5. Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples
http://www.sciencemag.org/content/349/6 ... 1.abstract
6. Host genetic variation impacts microbiome composition across human body sites
http://www.genomebiology.com/2015/16/1/191
7. mtDNA haplogroup and single nucleotide polymorphisms structure human microbiome communities
http://www.biomedcentral.com/1471-2164/15/257/
8. Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination
http://mbio.asm.org/content/6/3/e02513-14
9. Thesis MS unraveled, posting 10 August on
http://www.thisisms.com/forum/general-d ... 8-720.html
10. A Novel Probiotic Mixture Exerts a Therapeutic Effect on Experimental Autoimmune Encephalomyelitis Mediated by IL-10 Producing Regulatory T Cells
http://journals.plos.org/plosone/articl ... ne.0009009

[Leonard]

This groundbreaking article was published a few days ago and received wide press coverage.

http://www.cell.com/cell/fulltext/S0092 ... %2901481-6

The article was written by the same authors as Ref. 5 in the above posting and should be read in conjunction with it.

I quote from the discussion: Employing similar individualized prediction of nutritional effects on disease development and progression may also be valuable in rationally designing nutritional interventions in a variety of inflammatory, metabolic, and neoplastic multi-factorial disorders.

[Leonard]

I am progressive. Slowly, my gait goes worse, my legs go more difficult, climbing the stairs becomes more of a challenge. If I walk for a short while, making the next step becomes ever more difficult. But then, I stand still for some time, seconds or minutes. And the next steps will go remarkably easier. This was no different several years ago when I could still walk for several miles. If “flat”, I would rest a bit and things would go better again. During my holidays, if flat after a long walk, I eat some berries and grapes that I found on the way and I would go much better – almost instantaneously. Lately, also temperature and air pressure are influences that have becomer more pronounded.

Why do we see this recovery? How is the dynamics explained? It seems difficult to explain with demyelination which is a fairly static process. Myelin does not change overnight, let alone in a few minutes. As I said in an above posting, I think the real problem lies with the ion pump and more in particular the fact that the equilibrium can not be maintained. Probably because there is insufficient energy supplied to recharge.

Insufficiently functioning mitochondria disrupt the normal activity including that of the electron transport chain. And recharging the ion pump then fails or goes too slow to maintain firings. And the pump will then soon lack the ‘potential’ for new firings (up to 100,000 firings for fully charged pump).

The direction of causality is not immediately clear to me. It is suggested in the medical literature that the electron transport chain affects the ATP production and reactive oxygen species. But it could be different. The B cells problem with progressive MS seems clear and undisputed. The B cells may cause huge oxidative stress in cell membranes (the peroxynitrite from reaction with NO) and this might impair the working of the mitochondria and, when enough of them have failed (3000 to 5000 mitochondria per cell), the gradient ‘pressure’ becomes insufficient to recharge the cells for new firings.

These are some interesting pages on the supply of energy to the ion pump.
https://en.wikipedia.org/wiki/Electrochemical_gradient
https://sites.google.com/site/accessrev ... espiration

I am sure you will see demyelination in MS. But I tend to think about this as collateral damage. I think the real problem is ever weaker mitochondria that can not maintain the charge necessary for normal motor operation. It is a dynamic concept with energy supplied by the mitochondria. Such dynamic concept would be much more plausible than the static concept of demyelination and explain what we see and feel.

In the wider context of our evolving thinking about MS, I ask myself the question whether the old concept is fatally flawed? With dramatic consequences? I think it is.

[chenman]

Hi Leonard,
just a few thoughts from my side. Blood perfusion has been shown to be impaired in MS (lesions, white matter...). This is to be expected since small vein inflammation is at the heart of the MS pathophysiology, as I understand it (textbook knowledge).
If this inflammation can be stopped somehow (see below) the question is: will blood perfusion be restored to normal in the affected CNS areas? I doubt it, but who knows?

From my 20+ years of searching on the cause(s) of MS I am convinced that chronic infection with borreliae in active (inflammed) MS lesions is the cause:
http://link.springer.com/book/10.1007%2 ... 42-87571-7

If you scroll down to the chapter "Die Spirochaeta myelophthora" and click on "Look inside" you can see the spirochetes on the second page offered for chapter preview (p.37 of the book) in 16 micrographs from acive MS lesions. (No translatiion available.)
Author Prof. Gabriel Steiner (1883-1965) envisioned as early as the 1920s that a suitable antimicrobial would be the causal therapy for MS. He tried penicillin (effective in neurosyphylis) and early tetracyclines in the 1950s at Wayne University in Detroit, reported encouraging results in his 1962 book - but he was in his seventies at that time and does not seem to have published statistical evaluations. (Not even a biography of him is available: he has been forgotten, ignored...)

The problem: those drugs do not penetrate the BBB (at least not in sufficient quantities?). The drugs of choice, docycycline (later on minocycline) became available only after his death and were not tested in MS until the new century.
I started on doxycycline in Jan. 1996, as I have described in German for at least 15 years and started to describe in English in various places in the internet later on, on this board over the last few days.

As is "known" (but little recognized) hemosiderin from small bleedings in MS lesions has been described for many decades. Meanwhile deposited (presumably redox active) iron can be demonstrated by "high Tesla" MRI machines, even in CIS (i.e. by the group of Rohit Bakshi, Buffalo ---> Harvard).
Oxidative stress from redox active iron (Fenton reaction... ROS..) could support inflammation even after the causal borreliae have been eliminated.

Extracellular iron will be bound by transferrin and transported to the liver and bone marrow. This will be most effective with low transferrin saturation = TfS (a standard lab value in anlaysis of iron metabolism).

TfS can be reduced by depleting stored iron from the body, most effective via phlebotomies (= blood donations), the standard therapy of hereditary hemochromatosis.
I had serum ferritin of ca. 300 ng/ml and TfS of close to 40% in 1993, started a series of phlebotomies at the end of 1993. It took some time because my GP was "reluctant", but late in 1995 my ferritin was down below 15 ng/ml, less than 1/20 of the initial value. (TfS not tested, but probably below 15%.)

This low ferritin I have kept for almost two decades by now, mainly by 75 blood donations in about 15 years. I am pretty sure that this helped to clear iron from my CNS. (In 1993 a neurologist ordered a head CT which showed basal ganglia "calcification": this might be Morbus Fehr, and pathologist Fehr initially described this condition as "ferrocalcinosis", that is iron deposition in the basal ganglia, btw a - or possibly THE - cause of Parkinson..., if the Substantia nigra is severely affected. Hemosiderin is practically insoluble, so it may take many years to dissolve... This is a time horizon for one pathophysiological mechanism in MS which possibly has not been envisioned before?)

My suggestion not only for MS patients but every adult: "know your ferritin value", keep it low as in healthy children still growing (they need all the iron absorbed for growth), that is below ca. 20(...25) ng/ml, to be on the safe side.
Former Harvard medical chemistry Prof. Randall B. Lauffer wrote 3 books on healthy iron metabolism 1991-93. He possibly was the first to consider the role of "whole body iron stores" for neurodegeneration (Alzheimer, Parkinson, stroke): I strongly recommend the third book which was available used for 1c plus handling & postage, when I last looked up prices.

Certainly mitochondria etc. are of interest. But what counts are "simple" options to keep oxidative stress in the CNS low:
-- Stop chronic infection. (Doxycycline as agent of choice.)
-- Keep iron low (deplete, if already high), longterm, to avoid neurodegeneration (progression).
(I have read only very little of your very long thread - it is a problem of time, and I am slowed, probably because of the many scars in my brain, which I have to "think around"...)

Best wishes to you,
chenman

[Leonard]

Thanks chenman for your views.

Blood perfusion and iron accumulation are an issue. The immunity will weaken. I think in particular the immunity of the naso paharynx is an issue. And then things spread through the lymphatic system. That is when problems start.

The problem is a combination of HERV caused by insufficient epigenetic control and herpes EBV VZV.

Small vein inflammation is definitely a problem because cells change phenotype (HERV is somewhere on the divide between self and foreign).
T cells and B cells are called in.

I tend to see the vein inflammation as collateral damage. I believe the B cells cause huge oxidative stress with detrimental consequences for the working of the mitochondria. The charging of the ion pump slows down. And your motor functions will slow down, your eye nerve goes down etc.

As you have a German background, it should be welcomed if you would spread my thinking (posting 11 Nov) across German fora.

best, Leo

[Scott1]

Hi Leonard,

Sorry to hear things are not going so well for you.

Can I ask did you try doing it my way? i.e Valtrex, Q10, acetyl-L-carnitine,L-arginine, massage,Pilates. We are about the same age. I am continuing to get better. My only trouble issue is my blood pressure is prone to spike and it is uncomfortable enough to notice.
What you described is pretty much the way I see it. The things I take do help.

Regards,

[Leonard]

Thank you Scott. You're right, I need to work more on myself and do something. Because today it seems that I am just waiting for things to happen...

I am currently tossed up and down by on the one hand the desire to better understand MS and start a therapy from there (on the microbiome, a bit Wahls like) and on the other hand the ability to do something quickly with resources available today.

A few years ago I used valacyclovir, for two weeks. But I got spots in the groin, just as I had them in 2004 when I had the big flare up and MS was diagnosed. At the time of diagnosis I also had spots in the neck which is indicative for VZV. I was afraid for a reactivation of VZV which together with the HERV could do crazy things. I became cautious and stopped taking valacyclovir. Did you never experience any problems with that? CoQ10 and the other things that strengthen the mitochondrial working would seem ok to me. Methotrexate also goes with it.

Rituximab (intravenous and intrathecal) is another option that I have not completely scrapped from my list. I think that would work to stop my progression which I blame entirely on the B cells. A recent MRI has shown that the CNS lesions are stable for the last 7 years; I attribute my progression to spinal column lesions and B-cells, and; interestingly, to the muscles themselves that weaken (physio and NMES may help there). I see multiple experiments with Rituximab to deplete B cells in the Progressive MS Alliance. But it is expensive, and my insurance does not want to pay.

Endoxan also could be a possibility to stop the progression. And somewhere deep down, there is this hope that things will slow down or stop above 60 years of age (I am 59) because the B cell production will drop down. Without going into detail, I think that I can see several examples of that happening, in my own family (but not MS related) as well as in progression chart that was presented by Alan Thompson at the ECTRIMS 2015 conference.

As you are interested in the technicalities of the disease and how EBV primes the cells, this paper might interest you.
http://www.ncbi.nlm.nih.gov/books/NBK6235/

The word recombination is counted 13 times.

Just a few quotes:

The “pacification” of a retroviral gene is not straightforward. Retroviruses carry with them a number of cis- and trans-acting mechanisms optimized to suit a free-living exogenous virus, making them potentially dangerous to the host even after eons, when the integrated viral gene (“provirus”, or “virogene”) has been severely damaged. Eukaryotic cells probably have been exposed to retroelements since their very beginning. More than half of the human genome has probably undergone reverse transcription before incorporation. Thus, many defence mechanisms against damage from newly acquired retroelements must exist. Some are known. Methylation8 and inhibitory RNA9 are two of them. Previous ERV integrations may protect against new ones in several ways.10 However, in principle there are two major causes of disease; either i. there are adverse environmental influences, i.e., a conflict of interest between an invading microbe and the host, occasionally being negative for the host, or ii. there are imperfections in the host machinery itself, such disease being of a degenerative or chance nature. The subject of this essay has elements of both. We will discuss disease from the aspect of the interplay between host and retrovirus as a price for the evolutionary flexibility provided by the ERV.
...
HERV Polymorphism
HERVs, like other repetitive elements, can give rise to illegitimate homologous recombination (see below). This has been observed in the MHC region.68
Single nucleotide polymorphism (SNP) also occurs in HERVs.69-71 This is to be expected from genes who mostly mutate at a “pseudogene” rate.
...
Herpesvirus—ERV Interaction: Does EBV Use a HERV for Stimulation of B Cell Growth?
The suggested chain of effects is reminiscent of that of MMTV, which also activates a T cell to secrete B cell growth factors via a viral superantigen in order to stimulate growth of its host cell, the B cell. In this case, the benefactor allegedly is EBV.
...
Thus, it is not unlikely that these viruses may utilize each other. The love and hate relationship between the human organism and a HERV then becomes a triangle drama.In this review we have analysed the pathogenic potential of HERVs from an evolutionary perspective. Although the great majority of HERVs probably will prove not be pathogenic, there is now enough information to justify a search for correlation to human disease. There are leads for further research on seminoma, MS, schizophrenia, placental defects, gene loss and SLE.


best Leo