Theoretical Immunology

[Leonard]

@Vesta: Thank you for drawing my attention to the thread on the MSRV Rétrovirus, phase 2
http://www.thisisms.com/forum/drug-pipe ... 80-15.html

I think your understanding of studies that remnants of the Epstein Barr Virus (among others) imbedded themselves in human genes over millions of years of evolution is correct. A retired immunologist recently explained me exactly the same.

I find this information from the above mentioned thread most interesting: The sequencing of the human genome revealed human endogenous retroviruses (HERV) represent more than 8% of the human genome and result from the integration of exogenous retroviruses DNA during the primate evolution.

The information on this same posting from Fred1208 carries on by saying: MSRV is normally latent in the genome of individuals, but it can be re-activated by certain co-factors to expresses a pathogenic protein, MSRV-Env. Recent evidence has demonstrated that this ENV-protein is expressed in MS lesions from an early stage, is pro-inflammatory and inhibits remyelination.

The study that I quoted in my posting of March 12, here above, is precisely on this point. I will post it here again for ease of reference: http://www.ncbi.nlm.nih.gov/pubmed/23836485 And indeed, I found the study on the GeNeuro website.

@leonardo: I think EBV itself is the issue. Its envelop protein inhibits OPC differentiation and therefore should be earmarked as the direct cause of MS/demyelination. It could even be that the cross-reaction of immune complexes with the shared epitodes of remnants (what we know as autoimmunity or the action against the 'self') and the interaction with the fat metabolism (now subject to a lot of study e.g. from Buffalo) are secondary.

The fact that the EBV is on the OPCs is not a big surprise as such. The virus has learned to get on to stem cells because in that way replication becomes much easier.

Now on the question why the EBV can emerge as a chronic active disease, indeed a weakened immune system is the cause for not controlling EBV. And as you say, problems with the B-cells and T-cells come around the corner here. Again, EBV may play a double role here if it infects the stem cells of the bone marrow. And as we saw it has preference for stem cells. But also our diet, anti-oxidants etc are influences. It is a multi-facetted issue.

I think the CSF study you refer to also applies to MS and probably to a whole lot more. The site of GeNeuro is quite instructive.

@Anonymoose:

Hi Leonard & all,
I just find myself unable to apply further thought to the ebv/ms issue. As of now, there is no proof that ebv is running some of the ms shows. We don't know all that it does or how it works. Seems a fruitless labor for a lay person to try to figure out how it makes things go awry in some. The only thing that can be done is experimentation. So, I'm experimenting. It will be decades before they tie down all the ways in which ebv effects us. I'll just be happy with improvements/stability if any is to be had from an ebv killing crusade.

thank you. I am not sure whether it will be decades before they tie down, we live on Internet time. But just like you, I would be happy with improvements/stability if any is to be had from my Zovirax ebv killing campaign. The hope is that the chronic EBV disease will be pushed down and that then the immune system (that may also be EBV infected itself as well as the B-cells it produces) will regain strength to take over and keep the thing down.

I will let you know if there is anything to report but be prepared for a slow process, just as it came…

[Kronk]

The EBV virus angle is very interesting and a lot of parrallels can be drawn between MS and Chronic Active Epstein-Barr Virus Disease (CAEBV). They have even used MS meds such as the interferons on CAEBV patients with some success.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776035/

The GeNeuro link referenced by Leonardo above explaining the links between MSRV and MS
http://www.geneuro.com/en/technologies/ ... s_msrv.php

Also as I am always trying to tie together various successful methods of treating MS, the link below shows clear ties between EBV and Fatty Acids...
http://www.ncbi.nlm.nih.gov/pubmed/15047835

"...These results suggest that cellular Fatty Acid Synthase (FAS) activity is important for induction of Z transcription from the intact latent EBV genome, perhaps reflecting the involvement of lipid-derived signaling pathways or palmitoylated proteins. Furthermore, using FAS inhibitors may be a completely novel approach for blocking the lytic form of EBV replication..."

Palmitoylated proteins or palmitic acid is one of the highest on Dr. Swanks forbidden foods list.

[Leonard]

Over the last several years, I have had many aha moments when unravelling the disease.
It sort of started when I learned about ccsvi and met with Dr. Zamboni in the Autumn of 2009.
Clearly, I had to come from almost zero.
The Internet and these fora have been extremely helpful.

@Kronk: when I saw your posting above, I had another such aha moment.
I am referring in particular to the last link which suggests ties between EBV and Fatty Acids and to your observation of FAS on Swank's forbidden foods list. whow...
Thank you!

If you seach a bit on the herpes/HERV viruses and their life cycles, you find many very interesting articles.
Including on the latency, on the various stages in infection of cells, etc.
A whole new world of virology opens here.

I am sure that MS and its progression and the herpes/HERV viruses (including EBV) are strongly intertwined.
Actually, I find it strange that this path has never been pursued with more force.

[Kronk]

Thanks Leonardo. In my mind there is no question that, while there are many factors in MS, EBV may be the largest when looking at symptoms.

There are many links that keep popping up when researching EBV and MS. Below is an article linking EBV to immune inflammation, heart attacks and its onset caused by stress. It really shouldn't be a surprise then that the anti-depressant Prozac is effective in reducing lesions or points of inflammation in MS.

http://www.sciencedaily.com/releases/20 ... 162331.htm
http://www.dailymail.co.uk/health/artic ... erers.html

One of the big questions is that 95% of the world has EBV, but only a fraction of a percent turns into MS. I think this is due to genetics, in particular genetics that effect our enzyme profiles resulting in the excessive amount of lipids in our plasma which is required for lytic replication of EBV. There are likely many other genetic factors but the lipid profile is seen across the board in MS patients.

One exciting new avenue is that researchers have found EBV is responsible for 15% of cancers. This has spawned a great deal of research into EBV and ways to block its replication

http://www.infectagentscancer.com/content/9/1/8

[Leonard]

This is my best assessment of what is Multiple Sclerosis and what can be done.
I have amended the first posting on pg 1 accordingly.


1. Causes

MS has multiple aetiologies.

CCSVI (at least in part a birth defect) breaks tissue of the BBB (1)

Venous reflux/hypoperfusion:
- promotes local inflammatory processes (2)
- reactivates HERV-W (Herpes, VZV, EBV) in cerebral meninges (process as in cartilage of joints as in RA)

With broken BBB:
- Phase 1: Herpes simplex/VZV or Cpn blocks receptors --> inflammation --> RR (time constant days to weeks)
- Phase 2: EBV envelop protein inhibits OPC differentiation --> injury of cell types --> progressive (time constant months to years)

Graph of age of onset of MS has double peak: different mechanisms underlie Ph1 and Ph2;
Ph2 is age dependent, not on RR severity

(1) CCSVI = Venous insufficiency of Internal Jugular Veins (in the neck), draining the Cerebro Spinal
(2) Local inflammatory processes combined with inflammation induced high levels of nitric oxide cause narrowing of cerebral veins and autonomous nervous system dysfunction


2. Auto-immunity

Uncontrolled EBV infection reactivates in ectopic B-cell follicles in cerebral meninges --> chronically active EBV

Infection of autoreactive B-cells

Elevated EBV anti-bodies (already years before the first MS symptoms begin)

Cross-coupling of immune complexes with epitodes of remnant virus parts (in transgenic cells) explains the action against the "self"
- is secondary process (The MSRV-Env protein has also pro-inflammatory properties which translate into the production of different cytokines)
- EBV is chronic; immune complexes not effective against EBV

Note: Chronically active EBV presents
- coronary artery aneurysm (uncle, farther's cousin)
- nasopharyngeal carcinoma (grand farther)
- Meniere (farther)
- mitochondrial energy failure? (brother) is this CFS/EBV related?
- MS (me, with very high readings of Herpes simplex and EBV immune)


3. Weakening immune system

Immune system gets ever weaker; mitochondria get weaker
(poor quality of food e.g. high carb, lack of phytonutrients, stress, lack of sunshine/vit D/fat, environment, vaccinations, HERV/EBV) --> cytokine level chronically raised

Immune system is producing useless /non-working antibodies against EBV

B-lymphocytes unbridled multiplication

Hypo gamma globulin (shortage IgG3)

Immune system forgets about the rest

Chronic infection, for example:
- leaky gut --> Ɛ toxin
- mycoplasma
- Cpn infection (in RR)

Diagnosis:
- CFS
- Rheuma Arthritis
- Lupus
- MS

- Autonomic dysfunction smooth muscle layer
(my own titre was very high, eating own muscles, is this the regulatory system attempting to relax smooth muscle of cerebral veins?)


4. Treatment options

Gamma globulin IgG3 to help normalise the immune system

Vitamin D gut/immune system support

Nutritional support / diet
Detoxification for strong mitochondria; strong B-cells epithelium meninges
Anti oxidants MitoQ
High quality food phyto nutritients
Oxygen in bed room (when at rest in supine position)
Low fat / Swank / FAS = EBV inhibit (Fatty Acid Synthase inhibitor, no palmitoylated proteins, no palmitic acid)
Magnesium

Promote brain perfusion
stimulate Chinese 'axis'
Prozac derivative
Bosenthal

Hormonal support
DHEA
Testosterone
HPA axis
Adrenal – cortisol - gut

Anti viral (e.g. Zovirax/acyclovir or anti-HIV/HAART) ??
Anti biotics – Cpn RR

[Kronk]

Great synopsis leonard.

But I have to admit I dont understand the loyalty of many on the board for CCSVI. Multiple studies have found it to be equally rare in MS patients and the general public. Beyond that there isnt even a standardized ultrasound technique for determining who actual has it. And how much water a patient has to drink before the procedure can change their assessment from CCSVI to not. Hopefully the Canadian study will provide some conclusive answers but I wonder if everyone will accept the findings one way or the other.

[jerrygallow]

good point Kronk. I agree about CCSVI. Another angle I have thought about is that post op, people take blood thinners. If we have platelets that stick together, as Swank found, then why wouldn't that help explain some of the positive benefits people report. I know my vision improved a bit when I took bromelain, which also thins the fibrin in the blood.

[Leonard]

I think the story of MS is not a black and white picture, the disease is multi-facetted with many aetiologies, the diagnosis MS is only an umbrella. This means that the medical world has to think differently, that they have to thread in unchartered territory where they don't know. This is new to their world.

CCSVI is an example. If I take for a moment my own case: Azygos 50% blocked (cause unknown), right IJV over 90% blocked (kink in the neck vein as in the text books, probably a birth defect, one has to understand how veins grow), left IJV the dominant system blocked for 90% behind the left ear at the outlet of the cerebro (narrowing may well be EBV related at least in its final stages, my farther had Meniere behind the same ear which is considered to have an EBV relationship). So the picture may well evolve somewhat over time. The other observation is that, where it is not uncommon to have a dominant IJV, in my case the dominant left may well have developed because of a poor right, from foetus onwards.

I think the issue of gluten sensitivity is also a good example. The digestion of modern grain will certainly cause more problems for the intestines. The MS patient will not be intolerant to gluten as such but a weakened immune system and weakened endocrine system (e.g. cortisol) will cause a weakening of the gut wall and 'leakage' to occur much easier with devastating consequences.

I don't necessarily agree with the observations on CCSVI diagnosis. Last year my two eldest kids (in their early twenties) were checked on CCSVI with echo-Doppler ultra sound. I think this is the best technique, better than MRI. The doctor who carried out the tests must have seen over a thousand MS patients. My eldest kids don't have CCSVI, not even a sign of it. So they may get some autoimmune disease later in life because they will likely carry EBV and there may be some genetic predisposition but it won't be MS because the BBB will remain intact. In this regard, I think the medical sector can learn from our children.

But for now, it was the way in which the tests were done that give me the real comfort. The doctor explained to me what he saw, what happened if he pressed the IJVs by the pod and moved along them… For sure the CCSVI picture will not be black and white where water and blood thinners may have their effect but I think it is just wrong to say that CCSVI is equally rare in MS patients and the general public and that there is no good means for diagnosis.

[Leonard]

The above synopsis suggests a role for intravenous gamma globulin (IVIg) treatment in chronic progressive multiple sclerosis. In that regard, this paper may be of interest: http://link.springer.com/article/10.1007%2FBF00713862

The study shows a disparity between the post treatment EDSS score and the number of lesions from MRI after one year of treatment. In fact, the treatment resulted in lower EDSS scores while the number of lesions and the total lesion area had gone up. The authors suggest some effectiveness of IVIg treatment but the inverse trend shown by MRI analysis would indicate inefficiency.

But what do the results of the study imply? I think that there may be different mechanisms underlying the disability progression and the lesions, that the two are not necessarily fully correlated. As suggested in some of the above postings, the disability progression may be caused by the EBV envelop protein inhibiting OPC differentiation while Fatty Acid Synthase may have some connection to EBV replication; the lesions by the immune complexes with inevitably a connection to the fat metabolism.

If I take the positive results of IVIg treatment in CFS patients (also with a relation to EBV, magnesium deficiency, short of cortisol etc!), it seems not unlikely that IVIg treatment would also work for MS patients who suffer from a chronic EBV infection. It could help the immune system to regain control, including over the EBV. Inhibition of OPCs would slow down, and likewise disability progression, as suggested by the study results.

What lesson can be drawn? It would seem that lesions are not primarily connected to disability progression; there may be completely different mechanisms causing demyelination/nerve failure (EBV) and lesions. The sector should investigate with force what drives MS progression and the possible complementary role of IVIg treatment for progressive MS.

[Kronk]

...that there is no good means for diagnosis...

This is a good point, perhaps the most important issue with CCSVI. There is no definitive way to diagnose. Many researchers say it doesn’t even exist because of this fact.
I know that I have serious vertigo, light headedness and tunnel vision when I stand up quickly. Both when I had high BP 145/95 and even now that I have lowered it to 125/75 and am in excellent physical condition. I think there may be something to it call it CCSVI, blood hydrodynamics, etc.…

In relation to disability progression the research clearly points more to grey matter loss than to white matter lesions. The grey matter loss was originally identified by Jean Martin Charcot 140 years ago. The research to Grey matter loss in MS since is pitiful, and has almost exclusively focused on the white matter lesions. I found the study below very interesting which showed grey matter atrophy rates in various phases of MS vs. controls. RRMS 3.4x GM loss, SPMS 14x GMS loss. The white matter atrophy rate was 3x controls across all MS disease stages. It seems clear what is driving the root of MS disability.

http://www.ncbi.nlm.nih.gov/pubmed/18661561
Grey matter atrophy in MS

http://www.ncbi.nlm.nih.gov/pubmed/18570297
Gray matter atrophy is related to long-term disability in multiple sclerosis.

How to protect Grey matter
Testosterone – Proven, specifically in MS
Avoid Alcohol – Proven, your grey matter shrinks to protect against damage from alcohol
Vitamin B12 - Proven
Vitamin B6 - Proven
Exercise - Likely
Omega 3 – Likely
The list is long but the items above are just examples

http://www.realnatural.org/b-vitamins-r ... ogression/
B Vitamins and Grey matter

[jerrygallow]

leonard, I know this isn't a CCSVI thread, but can I ask you a quick question. I would like to have the doppler test done. Is that something I can pay for myself, and how does one go about doing it? I tried to look through the CCSVI section here, but I can't seem to navigate it very well. I have had some weird things with my neck veins. For example, I noticed even back in high school, that some days when I jogged in gym class, i would get pounding sensations in my head with each heart beat. I described it then as feeling like my brain bounced when I ran. Other days, it wasn't there.

Then I've noticed that I will sometimes feel an uncomfortable pressure feeling in my head and neck. When I push on my jugular, I can sometimes feel a pop, like a valve releasing? , maybe like a knuckle poping, and then the pressure and discomfort will disappear. It's worse on my right side. My first symptom was optic neuritis in my right eye. I'm curious how my veins would look, though I am skeptical about the CCSVI procedure itself. I don't know if any of this could be related to blood flow issues, or if it just sounds weird. Even now, when I do aerobics, some days I feel such painful headaches with each pulse beat, I have to stop. Other days, nothing at all.

[vesta]

CCSVI is an example. If I take for a moment my own case: Azygos 50% blocked (cause unknown), right IJV over 90% blocked (kink in the neck vein as in the text books, probably a birth defect, one has to understand how veins grow), left IJV the dominant system blocked for 90% behind the left ear at the outlet of the cerebro (narrowing may well be EBV related at least in its final stages, my farther had Meniere behind the same ear which is considered to have an EBV relationship). So the picture may well evolve somewhat over time. The other observation is that, where it is not uncommon to have a dominant IJV, in my case the dominant left may well have developed because of a poor right, from foetus onwards.

Hello Leonard: Were you treated with angioplasty for these blockages and what was your experience? Thanks

[Leonard]

where Zovirax might help, anti-HIV might also help.

with ref to http://www.ms-uk.org/bacteriaandviruses Could MS be caused by a retrovirus? (10/04/14)
I don't think that it is the remnants as such that get reactivated.
the remnants leave epitodes on the cell walls that are recognised by (cross couple with) EBV immune complexes.
so the EBV immune complexes cause what appears as the action against the 'self'; but this is not the cause of the demyelination.

the high EBV immune complexes are caused by a chronically active EBV infection.
the EBV is kept high through the fat metabolism (Fatty Acid Synthase) among other factors (here Swank may find an explanation).
the high EBV blocks the OPC differentiation and therefore dendrocytes are not replenished in time.
and then the nerves run back..

@kronk: I am not sure about the lesions as the cause for the MS disability progression. other people have lesions too (for instance people with mitochiondrial energy failure), some a lot more than the few I have but they do not develop the same disability. I think the EBV inhibition of OPC differentiation is probably more important for explaining disability progression. high EBV activity may be possible because the immune system does not work sufficiently. and mitochondrial failure may be a reason for that. and this same mitochondrial failure in some combination with the virus may also cause the lesions. but then to conclude that the lesions cause the disability is just wrong...

@jerrygallow: the echo-Doppler test is realiable; should be done by an experienced IR, a doctor who has seen many MS patients before. the cost here in Belgium is 40 Euro, about 50 US$, the test is done in 5-10 min's. whether to get ccsvi liberated is a next question, don't worry about that now, get diagnosed first.

@vesta: my IJVs were both opened, and have stayed open after 3 years. the experienced IR knows exactly what he is doing... the expectation is that they will remain open. the noise behind my ears disappeared, the heart beat in the ears during the night is gone. during the first 3 months, things went better. but then progression took over again, there is still progression. well, we know now it is the virus and the inhibition of the OPCs. when first liberated, enhanced blood flow will have improved dendrocytes in certain local areas and things went better in first but we know now that this is not good enough..

[Leonard]

from the other thread Could MS be caused by a retrovirus?

It doesn't seem to matter which way you join the dots, EBV always pops up.

I doubt solving the EBV part in isolation will deliver a final solution. The general condition is important as well. It's interesting to note that a treatment aimed at preserving immune function has positive effects.

Regards

I would agree. anti-viral alone won't do the trick and may give you a rough time (as Anonymoose put it). resurrecting the immune function will work towards the final solution.
strengthening mitochondria will be critical for that, i.e. antioxidants and phyto/micro nutritions that form the core of the Wahls diet.

these neurologists are thinking in the same direction:
http://www.msif.org/includes/documents/ ... al.pdf?f=1 where mitochondrial dysfunction gets mentioned
p18 Inflammation / degeneration overlaps with VZV / EBV; p 31 Moving to adaptive trials is progress; p59 EBV gets mentioned; but overall too much engraved in old thinking
http://www.slideshare.net/gavingiovanno ... oots-of-ms p51 the virus suddenly pops up putting many old MS believes in doubt / p55 Is the current dogma wrong. Is MS ready for a paradigm shift. the virus and anti-viral therapy get mentioned.
although the material is encouraging, in a Jan 2014 presentation (essentially the material from alan thompson here above), the agenda stretches out rather far, until 2023. I guess they haven't understood yet that we are on Internet time today...

[Leonard]

very useful information on EBV may be found on http://www.thisisms.com/forum/general-d ... 23331.html

I have been on Zovirax/aciclovar 2x800 mg/day for two weeks. I had no problems or side effects whatsoever during the cure itself. but now 4 weeks later I slide back, feel significant progression of the disease. wonder whether the anti-viral activity of aciclovar may be a factor increasing the production of immune cells (infected with EBV).. will get it tested soon. if increased, it would seem important for us to strenghten the immune system, not to attack the virus itself by anti-viral medication...

a lot of studies were done in the past with aciclovar and RR patients. but studies may not be telling for progressive. I think the mechanism and the state of tissues in progressive are distinctively different from RR (double peak in graph age of onset). and thus the effects of anti-viral medication may also be different...