Theoretical Immunology

[vesta]

I think here is real hope:
http://www.telegraph.co.uk/science/2016 ... after-gro/

Hello Leonard:

I think you are getting carried away with this HSCT study reported in The Lancet.

"The trial, which is the first in the world to show complete long-term remission from the debilitating disease has been hailed by experts as ‘exciting’ ‘unprecedented,’ and ‘close to curative.’"

It may be the first drug related trial but it isn't the first time one has enjoyed "long term remission from debilitating disease." What if all they are doing is inducing a massive detoxification with the HSCT? A good naturopath/kinesiologist can do the same without causing death from liver failure, or liver disease. In other words without poisoning the person. The patients were in an aggressive RRMS phase( early, not progressed) which is when natural Healing treatments are the most effective. Also, we don't know what the aftercare was. If they were put on a healthy Jimmy Scott, Terry Whals etc type diet naturally they wouldn't relapse. In some cases excess aspartame consumption will "cause" MS and getting off it will "cure" it.

This study is very limited (24 begin, one dies) and we don't know how they chose their subjects nor what the follow up care was.

In my opinion MSers would be better off following Matt Embry's Healing "recipe" http://www.mshope.com than subjecting themselves to drastic chemotherapy.

Best regards, Vesta

[Leonard]

HI FIRENDS
Please read
http://draxe.com/7-signs-symptoms-you-have-leaky-gut/
regards
seeva

Whether you have leaky gut or not and the degree of leaky gut can be tested from metabolites in the urine.
So if you are in doubt, get yourself tested.

I think the leaky gut is caused by a lack of IgA, the most abundant immunoglobulin in our body.
It has an important role in the arrest of toxins and viruses in the circulation.
People with a selective IgA deficiency have more risk to develop autoimmune diseases.

There is a link with the B-cells and Peyer's Patches: http://science.sciencemag.org/content/352/6287/aaf4822
and through that possibly a link with EBV.
But also there is an inter-relation with for instance iNOS and smooth muscles.

On the direction of causality, there is little to say at this point but I think the IgA production may well lie at the root or be close to it.
Definitely, IgA is a factor in the run up to MS and should be included in my thesis.

[Scott1]

Hi Leo,

I didn't quite follow the IgA argument. Can you expand on it a bit please?

Regards,

[Leonard]

Much attention has gone to the vascular connection, the endothelium, the virus and the microcellular environment. But a major component of MS is in the systemic/humoral immune system.

Viruses, in particular herpes strains, infect T- and B-cells and alter the immune response, to the benefit of the virus itself. This is the outcome of many tens of millions of years of our co-evolution with the virus. It is an evolutionary path that would preserve both the virus and our metabolism.

As a consequence of EBV infected B-cells, critical processes such as class switching from IgM to IgA could be distorted leading to a selective IgA deficiency. A selective IgA deficiency is associated with autoimmunity and considered a risk factor for the development of autoimmune diseases such as Lupus, Rheuma Arthritis or indeed MS.
http://www.ncbi.nlm.nih.gov/pubmed/27174992
http://science.sciencemag.org/content/352/6287/aaf4822

The small publication under the link below suggests a number of hypotheses to account for the association between IgA deficiency and the presence of autoimmunity. But in fact the autoimmune reaction we see might well be a combination of all hypotheses. Where of course the interaction of the virus with HERV segments and toxins makes cells change phenotype which leads to a breach of immune tolerance causing interactions with the immune system.
http://apps.elsevier.es/watermark/ctl_s ... f001_2.pdf

Therefore, there may be a direct association between EBV infected B-cells and an IgA deficiency in the genesis of autoimmunity. Possibly other Ig’s are also deficient or non-working. Such course that would help the virus would not be entirely unlogical from an evolutionary perspective. It would cause a generally weakened immunity that finds its origins in the intestine and Peyer’s Patches. Where the intestine is the central organ regulating our immunity.

But there is more to it, and this is somewhat paradoxical. This is the effect of immunosenescence, say the aging of the immune system. With rising age, a large number of immunological changes occur which – with the strong viral connection in mind – now needs to be seen in a completely different light. The Handbook on Immunosenescence under the link below already gives several hints to immune system dealings with the virus and how this changes with aging.
https://books.google.be/books?id=VY_8Yf ... ol&f=false

At around 60 years of age, it is known that the production if B-cells wanes. And with that also the mechanism underlying the progression ceases. By that time, the inflammatory component has also waned. That is why there are no new cases of MS reported after 60. And people stabilize: see e.g. the graph at min 5:00 of this video.

Now, despite the reduction of B-cells, the production of IgA serum and other Ig’s increases. See also pg 32 and further of the above Handbook. Hence, there is not a simple causal or linear relationship between B-cells working on Peyer’s Patches and IgA production. In fact, a highly non-linear process with multiple variables may well be involved in our immune aging and viral control, a system of an enormous complexity.

We may well be a long way off understanding this enormous complexity. Notwithstanding, a total system reboot may be possible through chemo and a Hematopoietic Stem Cell Transplantation (HSCT) where one deletes the infected immune cells and starts with ‘clean’ baby immune cells. It's bit like rebooting your computer after it crashed. You don't understand exactly where the system was hanging when it crashed, but you force a 'clean' start.

Chemo with HSCT is possibly leapfrogging the complex and ill-understood world of immuno senescence and viral control. And in this way, we may be able to force an effective solution (a cure) without necessarily understanding all the complexities involved. This is precisely what we see happen now, see e.g. the testimonial of Vicki Taylor Wilson who had PP-MS on https://kickinms.com/2016/08/30/3-years ... -for-ppms/ See also the next posting with a quote on HSCT that I found on an other forum.

[Leonard]

with ref. to http://www.macleans.ca/society/health/a ... t-so-fast/ which takes a fairly negative stance on HSCT for MS:

This is not a news article, it is an editorial. As such, it is not impartial, nor objective, instead reflecting the bias of unfactual opinion. It heavily references very old, outdated and irrelevant data, especially in terms of treatment safety.

From a previous post relevant to this. . . . The big three lies of ignorant neurologists that I see time after time (are they afraid to admit they don't know, or do they have some other ulterior motive? I have no idea). . . . . . .

#1 HSCT is experimental (WRONG! HSCT has been performed more than two million times since 1967 and is currently performed more then 50,000 times every year all around the world for cancer. HSCT is NOT experimental; it is a well established and well understood legitimate routine medical procedure performed daily around the world).

#2 HSCT has not been shown to be effective for MS and people relapse soon after treatment (WRONG! HSCT is so far the MOST beneficially effective demonstrated treatment to durably halt the underlying disease activity & progression of MS and other hematologically-rooted autoimmune diseases and people have now exceeded well more than a decade of complete disease remission),

#3 The absolute biggest lie of them all; HSCT is dangerous and will probably kill you (Super WRONG! Autologous HSCT as utilized for treatment of MS and other autoimmune disorders is safer than regularly driving/riding in an automobile). . .

And that's the most important thing learned from all the years of HSCT clinical study work. . . . HSCT performed earlier in the course of the disease is nearly universally more beneficially effective compared to transplanting later in the disease evolution when there is a greater degree of irreversible disability. Lesson learned: don't wait until it's too late. . .

[Leonard]

This is it!

VZV causes microbleedings and with that a breakdown of the blood-brain-barrier. This results in the inflammation. T cells are involved, with delay.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814602/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936337/

Then the path is paved for EBV to anchor itself on those places where the BBB is broken (quote from the article below .... inconsistent detection of EBV in MS brains ...) and B-cells to interact and cause progression. Where onset of EBV related progression is more age dependent (see 2nd article below).
http://www.sciencedirect.com/science/ar ... 8213001605
http://www.ncbi.nlm.nih.gov/pubmed/22736750

Besides a cellular immunity component, there is a systemic component in the chain. Where herpes infected T cells cause or help EBV B cell replication or at least do not contain the process (see e.g. the thesis).
The book Primary Immunodeficiency Diseases: a Molecular and Genetic Approach expands on how T-cells may contribute to the development of EBV-associated B-cell diseases.
This article http://www.jimmunol.org/content/171/2/886.full.pdf also talks on the clever strategy developed by the virus which allows viral persistence, on the many events triggered by CD40-CD40L interactions between B and T cells etc.
[added Nov 18: see also http://multiple-sclerosis-research.blog ... cells.html ]

Furthermore, it can not be excluded that EBV infected B cells affect Ig class switching and thus in turn give room to a spreading of other herpes virinae.

What becomes clear is that we are far from understanding the enormous complexities involved in intra-immune system interactions in response to herpes virinae.
Notwithstanding, evidences are accumulating that a total system reset as in HSCT works for both the aggressive and progressive forms of MS.

[Leonard]

The matter including the thesis http://www.mshackathon.nl/wp-content/up ... ressed.pdf should now be encapsulated as follows:

- the co-evolution of herpes and the immune system (or how the virus "dances" with the immune system)

- the central role of the gut in our immunity (microbiome compositional patterns; Peyer's Patches, interactions)

- immunosenescence and viral control (chapter 2 Handbook on Immunosenescence)

- HERV activation, interactions, the breach of tolerance, autoimmunity and cancers

- MS: herpes and cellular & systemic immunity (VZV mocuepithelial & T-cells; EBV B-cells & epithelial cells, other factors as ccsvi, nasopharynx, brain-bowel)
[Table 43 - 1 of https://books.google.be/books?id=Gx3mCg ... ls&f=false ]

- treatment options (chemo (cyclophosphamide) + mabs/rATG + aHSCT; multiple light chemo cycles (cyclophosphamide) possibly with mabs/rATG and followed by anti-HERV/detox green diet (Wahls); early on: anti-viral (acyclovir) and interferons, Swank low saturated fat diet)

[Leonard]

HSCT has been applied for MS for over 10 years, that's not new. What is new here is that, although only a poster study at this stage, the matter is now seen to enter the main arena of the neurologists, that’s ECTRIMS/ACTRIMS.
https://www.msconnection.org/Blog/Septe ... rrow-Trans
http://www.medpagetoday.com/masters-of- ... n-ms/60256
https://multiplesclerosisnewstoday.com/ ... ransplants

Thoughts of neurologists have been controlled by the singular monolithic structure of ECTRIMS/ACTRIMS for too long, with a focus on Disease Modifying Treatments (DMTs). And neurologists could not escape. So the fact that it is there now and gets some visibility is great news.

The debate though is still not very sane, influenced by other factors such as exaggerated risks of chemo/HSCT, an undue emphasis on very aggressive MS and a call for randomized control studies (RCTs) to compare with the regular DMTs. Probably there is a subtle steer here to delay, deter, defer, …

But neurologists should make up their own mind. Risk has come down considerably over the last decade; DMTs are not a full and viable alternative; although may be not as spectacular, chemo/HSCT also works for the progressive form. What’s more, one could use historic data from studies of DMTs with many thousands of patients as a basis for comparison, obviating the need for RCTs.

The Quality of Life (QoL) of the patient has been omitted as a factor in the equation, but should become the main and overriding criterion. Chemo with HSCT should be offered as the most effective treatment for MS. Where it is unethical for neurologists not to offer HSCT.
http://tidsskriftet.no/node/23437

[Leonard]

In my posting of June 21 above, it was assumed that B cells would normally be involved in IgA class switching, that B cells normally interact with Peyer's Patches. Such believe may find its origin in the fact that EBV is such a ubiquitous virus that most people show some form of interaction. But this is not necessarily the normal situation and hence the thinking behind this article may be fundamentally flawed http://science.sciencemag.org/content/352/6287/aaf4822

It may well be that in the normal situation, such interaction is not there. But that over time, when more and more B-cells get EBV infected, they impair class switching and an IgA deficiency develops over one's life time [and a bad gut develops, and the second peak in the graph of the age of onset shows up]. Such course would seem a logical evolutionary path that would benefit the virus. On processes how the virus gains access to the long-lived pool of memory B-cells, see for instance http://www.jimmunol.org/content/171/2/886.full.pdf

Such conceptual thinking would be entirely consistent with the phenomenon of increasing Ig's with age when the B-cell production drops down above 60. A reduction of B-cells at age 60 would lead to a gradual reduction of EBV-infected B cells and with that a recovery or increase in IgA production above age 60 which is exactly what we see happen.

This is but one of the mechanisms by which the herpes virinae get hold of the immune system. There may be other clever strategies that the virus has developed for its own benefit. See also the above posting of 10 Aug on the co-evolution of herpes and the immune system.

[Leonard]

Hi Scott, I hope you still read here.

Recently, my mother brought to my attention that her mother died with/from psoriasis. An autoimmune disease with a clear link to herpes virinae.
Now from my farther's side, his farther died from a naso pharyngeal carcinoma. There is clearly the EBV relationship. I have reported that here several times.
So I may have inherited a poor control of herpes virinae from both farther's and mother's side.

As well, my family lived for generations in the shadow of the heavy metal industry.
I had the ccsvi, a blocked internal jugular vein on the right side (a truncation in the low neck, probably a birth defect) and a blocked internal jugular vein on the left side (behind the left ear, the left vein was dominant and may have developed like that in a very early stage because of the truncation in the right vein, the stenosis is possibly herpes zoster caused).

Add it all up, and it was too much. I got MS.

I would be interested to know whether you see similar 'viral death' causes in your family going back to the grandparents.
And of course, any one else who reads here and wishes to comment, please don't hesitate.
I think it is important for all of us to get the viral connection clear.

Best, Leo

[Leonard]

In order to heal from MS, one should work on both sides of autoimmunity, that is:
- To deplete bad virally infected T/B immune cells and grow new ones; and
- To silence the HERV expression in endothelial cells.

The essential part of correcting the systemic immune system is chemo. No chemo, no cure. Cyclophosphamide eliminates bad T/B cells and induces growth factors to grow new immune cells (see Mechanisms of Action on https://en.wikipedia.org/wiki/Cyclophosphamide ) I see this is sometimes augmented with mabs (Rituximab/Ocrelizumab) and rATG to deplete B cells.

A number of short ‘light’ cycles of cyclophosphamide (4 to 8 ) would seem effective. A ‘heavier’ chemo regime (as with aHSCT) might even be more risky, of creating hidden viral niches and causing other damage to the patient.

This would seem to imply that the stemcel transplantation procedure (aHSCT) is perhaps not strictly necessary. Richard Burt / Chicago confirms this: see min 55 of this video

I can recommend Burt’s video. It’s great, genuine, sincere, balanced. Also watch the questions and answers towards the end, when he compares Lemtrada with chemo, his comments on the mind frame in the sector and the resistance to change that comes from the academic world...

The other cornerstone of an MS therapy is to silence the HERV. The anti-HERV is achieved through the gut microbiome e.g. the Wahls ‘green’ diet. A good diet will also help with detoxification. Other evidences are currently accumulating that autoimmune diseases such as diabetes 2 can be controlled by dietary change.

Incidently, Terry Wahls also had several cycles of chemo before she started the diet. Where I am sure it was the combination of chemo and diet that got her out of the wheelchair.

Of course, physiotherapy, anti virals, methotrexate (to oil the cell machinery) etc can all help to speed recovery.

-----

I am just a simple guy who looked with a pair of fresh eyes at the problem, a patient in crisis who felt free to let his thoughts go out.
I realise that I may have lost many of you on the way, for which I am sorry.

This is as far as I can get it. I am sure there are quite some valuable ideas in this thread.
It is now for others to pick them up and to do something useful with it.

[Leonard]

On the other thread on EBV targeting treatment yields clinical improvements in spms, there is a discussion on the role of EBV B cells and citrullination (foreign DNA).
http://multiple-sclerosis-research.blog ... cells.html

My view on this matter is as follows:

The EBV virus is ubiquitous.
I was told by an expert virologist that a high count of EBV immune complexes (from EBV B cells) in the general population is not at all unusual.
But a high count of EBV B cells alone is not enough to get MS.

There is something else that is needed.
Cells in the endothelium need to express themselves, that is a necessary condition.
So you need both: the EBV B cells and cells in the endothelium that are activated.

Our cells express themselves if HERV segments in the cells are activated.
A bad gut may trigger the HERV expression; a healthy microbiome silences the HERV segments.

Transgenic cells change phenotype, shed cytokines and chemokines.
This alerts the immune system.
At that point, you may get a cross-reaction of the EBV B cells with the transgenic cells if the B-cells find common epitopes.

And indeed, the EBV B cells find common epitopes because EBV may have anchored itself already in an earlier phase in the cells.
In periods of immune deficiency (foetal period, newborn period, transient immuno deficiency periods caused by Zoster/VZV is an immune suppressive virus (e.g. period of dry eyes), ccsvi/hypoperfusion is a factor too causing weakened immunity of the naso-pharynx in an area just below the CNS), EBV may have settled its proteins in permissible cells. [OPCs are such cells because they divide fast and after millions of years the virus has learned to go there]
VZV may have broken (selectively) the BBB prior to EBV infection.
At that point, the person became predisposed, but cells were still recognised as self. Transgenic subjects may be healthy for life.

Up to the point where the cells are activated.
In the case of MS, herpes virinae may work together to weaken immunity in the gut (Peyer's Patches, micro-biome, interaction T/B cells).
http://www.cnbc.com/2016/12/01/parkinso ... teria.html
[[ https://multiplesclerosisnewstoday.com/ ... -sclerosis ]]
http://apps.elsevier.es/watermark/ctl_s ... f001_2.pdf
And the activation of transgenic cells follows when the microbiome gets distorted and no longer silences the HERV.

When the cell is activated and changes phenotype, the specific immune response against the EBV infectious agent (the EBV B cells) will now cross-react with the transgenic cells that were EBV infected (because they find common epitopes).
This is causing infiltration of active immune cells and/or the release of superoxide.

For the progressive form, membranes are affected by the peroxynitrite (which is the product of superoxide with NO), mitochondria slow down, insufficient ATP is produced in the cell, the ion pump lacks the fuel/energy to pump, sensory and motor functions fail.
And you have progressive MS.

Perhaps the citrullination has something to do with cells changing phenotype.
From a quick search I find a link between citrullination and SNPs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108877/
Myelin Basic Protein as a Novel Genetic Risk Factor in Rheumatoid Arthritis—A Genome-Wide Study Combined with Immunological Analyses
For SNPs, see also my thesis on http://www.mshackathon.nl/wp-content/up ... ressed.pdf

Furthermore, I think the relationship of citrulline and NO is not a direct relationship. https://en.wikipedia.org/wiki/Citrullination
It might well be that EBV B cells are the necessary intermediate step, that they are triggered as described, release their superoxide causing a reaction with the NO. Where things as cause and effect are greatly mixed up.

I should be happy to get your views and/or comments.

[Scott1]

Hi Leo,

I missed your post from 3 October. I agree that defects handed down can leave you compromised from the beginning.
In my case, My Father died when I was eight (1965) as a results of insults to his body as a prisoner on the Burma railway and my Mother had rheumatic fever as a child and TB in her 20's. I was was bred from people who had been compromised. In particular, my mother displayed many symptoms of fatigue, cramps and illnesses that were suspiciously like someone who was on their way to MS. If I got her mitochondria it wouldn't have helped. My Father was fattened up to 6 and a half stone 12 months after the war and discharged as medically fit. Goodness knows what could have changed in his metabolism.

On your most recent post, Brett from MStranslate has publish a clear explanation of the basic EBV models for those who are new to this thinking. I am a huge believer in EBV having a role and that's why I still take valacyclovir.

This link goes to his site http://www.mstranslate.com.au/ms-epstei ... te-part-2/ . he also had a number of interesting presentations on the mitochondria last week.

Regards,

[NHE]

If I got her mitochondria it wouldn't have helped.

Mitochondria are always inherited from the mother. The sperm is just a DNA delivery truck.

[Scott1]

Thanks,

I thought so but wasn't sure.

At least we are trucks, not vans!