Theoretical Immunology

[vesta]

Leonard: Thanks for the great quotes. Vesta

[Leonard]

I am starting to realize that the international scientific community is apparently not able to organize the scientific discourse on treatment strategies for MS.

The quasi-monopoly of ECTRIMS / ACTRIMS - the global conference for MS - and perverse drivers in the system have led to a massive systemic failure. This failure becomes all the more clear by the recent new initiative aimed to address progressive MS which, after only 1 year, comes up with this very positive report: http://www.nationalmssociety.org/Nation ... -final.pdf

I think the failure is such that this would warrant an anti-trust investigation by the authorities in the US and in Europe. Anti-trust law is very powerful and is there to protect the citizen. Although the case may not necessarily be anti-competitive as such, there is at least the smell of a bigger cartel and collusive practices that have inappropriately focused the agenda of the international scientific community on the inflammatory phase of MS for many years.

Thank you very much National MS Society of the US for putting the report on your website, this is courageous! In our countries on the other side of the pond, it is completely silent. Our MS associations participate in the Alliance and participated in the Boston meeting but apparently the messages don’t suit them that well. To be honest, I have often wondered what these societies are really doing and where is the patient.

How far and how fast this new alliance may take the matter forward remains to be seen. The alliance is embedded in the typical neurological field (where MS is of a different virological origin, see above), the case remains extremely viscous and progress undoubtedly will find many bears on the trail.

But this is what happens when the old world is caught by surprise by the Internet where new concepts emerge such as my thesis above. Treatment strategies supporting these new concepts (e.g. chemo to deplete immortalized B-cells) should be tested with urgency. I think here the current double blinded randomized trials regime is inappropriate and just helps the old world to consolidate its position. One person trials may be much more effective and faster: http://www.nature.com/news/personalized ... ls-1.17411 where the Internet offers plenty of means to coordinate. The trials regime (in Europe regulated by the Clinical Trials Directive) will need to be revisited with great urgency. About a year or so ago, there was an article in The Lancet with that same message.


There is a lot to think about.

[Leonard]

This study on antivirus immune activity in multiple sclerosis that I found on the other thread is highly relevant to our case.
http://www.ncbi.nlm.nih.gov/pubmed/25939660

The study nicely aligns with the above thesis on a new vision on MS with a central role for EBV (see posting 26 March on previous page 46).
Slowly, slowly, things seem to be moving...

[Leonard]

From the other thread on EBV targeting treatment yields clinical improvements in spms:

Health care in Canada is very insular and sensitive to turf trespassers. The attitude I have seen is that since "MS" is not considered as a fatal condition, there can be no off-label or experimental treatment for it. Basically the "MS" group of patiemts is seen as a gravy train for the drug/research medico-industrial complex. It is not meddled with, without all i's dotted, t's crossed, all three phases of trials, and approval by the FDA and Health Canada. If I could find such an oncologist or anybody willing to administer some kind of EVB targeted therapy, it would likely be in the US, and cost me a lot of money, even though I am supposedly insured. I could not only be playing guitar, I could be driving to the six-figure job I had, but the insurance company won't move without the medical mafia's approval.

...

There are those who are shot and killed in the hours before an armistice comes into force.

I am afraid this is not only true for Canada. Seeking treatment with Rituximab ( http://en.wikipedia.org/wiki/Rituximab MS is explicitly mentioned) and Methotrexate ( http://en.wikipedia.org/wiki/Methotrexate MS is explicitly mentioned), I am finding out the hard way that this is probably true for most places in Europe as well.

[Leonard]

Thinking this matter over a few times, I believe that perhaps MS is not caused by an external source such as a virus (EBV) but that this virus triggers a certain process in the cells. The removal of the 'start-up' of that process will not stop the progression. To stop that, you would need to be with that “certain” process.

I think that certain process may well be the intra-cellular fat and protein metabolism. Preincubation of cells with EBV primes the cells that, when stimulated, start a response that leads to the release of pro-inflammatory lipid mediators such as arachidonic acid. This article suggests a role for EBV to activate intra-cellular events leading to the release of pro-inflammatory mediators.
http://www.ncbi.nlm.nih.gov/pubmed/11737068

We know that it is possible to get some form of control over the inflammatory disease through diet and medication. The low saturated fat Swank diet and the anti-inflammatory properties of HDL seem to confirm the involvement of the fat metabolism on endothelial function and viral activity. In addition, administration of Metformin and Simvastatin seems to reduce cellular shrinkage, presumably by reducing oxidative LDL.

In MS, the ratio Omega-3 to Omega-6 changed where the ApoA1 level is reduced (25% in RR, 50% is SP and 75% in PP). ApoA1 is anti-inflammatory (Omega 3) while it is often said that Omega 6 is pro-inflammatory. I do not exclude the possibility that Omega 6 is neutral, but that it just looks inflammatory because viral activity is not inhibited like it is with ApoA1.

Several studies have concluded that the plasma of people with MS has too much saturated fat. Saturated fat is critically important in cell production making up to 50% of the cell membrane and giving it rigidity. The cell membrane is selectively permeable, determined by the ratio of saturated to unsaturated fatty acids. Additional unsaturated fats increase the fluidity and therefore the permeability of the cell. Whereas additional saturated fats increase the rigidity of the cell. Too much saturated fats and the cell would be effectively sealed off, limiting the binding of cells to interact with or produce immune modulating hormones. The balance thus is very important for cellular homeostasis.

This study suggests that the consumption of a saturated fat reduces the anti-inflammatory potential of HDL and impairs arterial endothelial function. In contrast, the anti-inflammatory activity of HDL improves after consumption of polyunsaturated fat. These findings highlight novel mechanisms by which different dietary fatty acids may influence key atherogenic processes.
http://www.ncbi.nlm.nih.gov/pubmed/16904539

I am fascinated by this article on the protein ApoA1. Apolipoprotein A1 is the major protein component of high density lipoprotein (HDL) in plasma. http://en.wikipedia.org/wiki/Apolipoprotein_A1 It has a specific role in the lipid metabolism. A recent report suggest that ApoA1 mRNA is regulated by endogenously expressed antisense RNA.
http://www.cell.com/cell-reports/abstra ... all%3Dtrue

Is this antisense RNA the key to the anti-inflammatory properties?


The interactive pathway map on this page http://en.wikipedia.org/wiki/APOA2 shows a highly complex and intertwined fat metabolism or at least what has been understood of it. Click on the figure and it unfolds; click on genes, proteins and metabolites for further detailed information.

Perhaps what we need now is a new conceptualization of cellular fat and protein metabolism to take account of the novel findings on antisense RNA and the significant local modulatory effects of long noncoding antisense RNAs.

[Leonard]

From http://www.thisisms.com/forum/general-d ... 26349.html and http://www.ms-uk.org/bacteriaandviruses :

I think gut bacteria constitute the immune system. Bad gut, bad immunity.

With bad immunity, the herpes virus that is with us for 1 Billion years and EBV that is with us for 40 Million years show up. By lack of control.

With herpes and in particular EBV, strange things happen. The immune system played a cat and mouse game all the time and is fully 'intertwined' with the virus and the cellular metabolism.

The EBV misguides the immune system. EBV primed cells (or should I say herpes primed cells here?) then through the fat/protein metabolism respond and inflammate. The two are intertwined: misguided immune system, high concentration B-cells, superoxyde, low ATP/AMP, low interferon alpha and viral control, adonesine, poor functioning cell machinery.

The nerve cells are affected early on, across the body. The ion pump needs most cellular energy, it needs well functioning mitochondria. When mitochondria weaken, the equilibrium (charging) of the pump can not be maintained and nerve conduction runs down.

The system inflammates, the nervous paths can not be maintained, and you have MS.

[Leonard]

From the other thread Researchers solve MS 'puzzle' on http://www.thisisms.com/forum/general-d ... 26348.html :

I think the T-cells are drawn in with the B-cells that cross-react with the transgenes in the OPCs. During this cross-reaction, many mediators will be released by the infiltrating T-cells.

This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS. There may be some specific features of T-cells observed in MS.

As regards the EAE mouse model, EBV is not part of it. The ERV is found in mice, the HERV and EBV only in primates. EBV is central to the B-cell complex of problems in MS.

What is happening here is that the Internet comes loose from or transcends the old world. As 1eye sais, they are still flogging the bankrupt, useless EAE "model". When Hafler says (as in the above link) "in MS patients they do damage to the nervous system", neurologists are hopeless with no chance because they only look at the result without understanding what happens before that has nothing to do with the nerves.

[Leonard]

In trying to understand how EBV primes cells to change the internal cellular metabolism, we come into the field of epigenetics.

Epigenetics represents an evolving frontier for the development of therapeutics for the control of cancers and inflammatory (autoimmune) and neurological diseases including multiple sclerosis.

After neurology, endocrinology, gastroenterology, immunology, virology, we entering here a fascinating new field, that of epigenetics.
See for instance http://en.wikipedia.org/wiki/Epigenetics

This article on "Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies" specifically mentions multiple sclerosis:
http://www.ncbi.nlm.nih.gov/pubmed/19833297

A good research article linking the herpes virus infection with epigenetics may be found here:
http://www.researchgate.net/profile/Dav ... 1dc0e1.pdf

I have not understood this latter article entirely but mention is made of primers. I wondered whether there could be any overlap or common factor with the EBV cell priming. Is cell priming happening at a molecular level?

Interestingly, the article also mentions inhibitors that inhibit LSD1 activity such as MAOIs. MAOIs are monoamine oxidase inhibitors linking things to the oxidation state of atoms.

Using MAOIs, medication on the market for depression, doctors were able to block herpes simplex viruses (and EBV?) from using a person's cell machinery.
http://www.wwltv.com/story/news/2014/12 ... /19917107/

Extending the thinking (=my own wild thinking, right or wrong), perhaps then MAOIs would also be able to block oxidation of virus primed cells in an environment with huge EBV B-cell originated oxidative stress.

I would be interested in any observation you might have. Scott, Kronk, Anonymoose, any views?

[Anonymoose]

I think we are getting lost in minutiae again. We need to ask ourselves why pwms have a problem managing ebv loads (low ebv specific cd8+ T cells). I believe this is just another part of "the cascade." Yes, lessening ebv load does help lessen ms symptoms as shown in Pender's adoptive immunotherapy case study and the positive results witnessed with use of rituxan but neither of those courses of treatment completely or permanently resolves our problem with ebv or ms. We have to find the root cause of our failure to manage ebv.

Loads of people are infected with ebv and carry hervs. Most of them do not have ms or any other neurodegenerative disease. What do we have that makes a common harmless infection such an insurmountable challenge to our own immune systems? My guess is stealth co-infections...some of which aren't even known yet. I think we need to apply a broad spectrum (NOT antibiotic based) protocol to help our immune systems manage any infection and by doing so we will gradually bring ebv and "ms" under control. That's my theory du jour anyway and since I spent yesterday writhing in herx pain and fever on Buhner's core Lyme protocol plus a bit, I'm thinking there might be something to it.

Keep digging but don't go too deep!!

[Leonard]

Anonymoose, thank you. I share your view that we should not get lost in minutiae. And that we should "paint with the broad brush" i.e. (my interpretation) by taking chemo to kill off all infections.

Notwithstanding, it may be useful to explore new lines of thinking a bit further. When I started here in 2011, I knew hardly anything about the human body. I had this gut feeling that the phases of MS were caused by different underlying mechanisms. We know now this is the case and why. The same may be true for the epigenetics. It is what Buhner writes in his book: When a lot of people with a lot of motivation begin looking around themselves, searching for answers, they come up with some truly amazing things. If you lock people in a room with four ways out, someone will find a fifth way out. Always.

One very interesting test and very simple to carry out would be as follows: If you look at the people diagnosed with MS, a small proportion never develops progressive MS. It would be very interesting to analyse these patients in their 50's to see whether they have EBV in their blood. My gut feeling tells me they don't! The herpes simplex and possibly VZV causes the inflammatory stage. But they don't progress because they don't have EBV. They are among the 5-10% of population who do not carry EBV.

[Anonymoose]

Leonard,
Do you worry about letting infections run amok by completely obliterating the immune system with chemo? Infectious agents are everywhere in us, not just in chemo targets. I'd think we'd be dead if we killed off all cells that could possibly be infected. Also, I have the feeling that some infection did run amok in me after my rituxan protocol. Despite the fact that I did experience lasting improvement from the treatment, my labs and fluctuating well-being in non-ms ways indicate something not good was happening while I improved in other ways.

That would be a lucrative experiment to examine those who don't convert to progressive ms...if the researcher were more open minded and knowledgable about stealth infection. It's funny that you never hear about some ms findings until you go looking for them...spirochetes and ms come to mind. You could be right about the lack of ebv in those that don't phase out to progressive. If that were the case, why would rituxan be so effective for rrms? Ebv seems like part of the precursor to spms. Maybe we could jump the gun and study those who aren't at all improved with rituxan? I'd more likely think ppms could be lacking the ebv involvement but then ppms is likely a completely different beast anyway. What a mess! To add to the confusion, "ms" could be any combination of infections which would explain the differences in presentation and progression (which obviously would also be influenced by meds, diet, gut flora, etc).

I don't know if it will work, but Buhner is a lot more accessible and easy on your wallet than chemo. Some of his components also fight ebv like his Japanese knotweed based resveratrol dosing. I plan on mucking through the Lyme core and adding the other protocols for all the other infections as I go along. I can't just sit on my rump waiting for my ebv load to crawl back up and start causing problems again.

I hope you get more on topic responses to your question from kronk and scott1...you know I've an impossible one track mind and can never be swayed off course until I sway myself. My fifth way out of the room would probably be saying "Beam me up, Scotti!" over and over again until the others in the room with me were so annoyed they vaporized me with glares and I seeped out of the room through a crack in the ceiling.

Be well!

[Scott1]

Hi Everyone,

I think Leonard has raised an interesting point. The issue will be contraindications (eg Baclofen is no go).
My own preference would be to look for coinfections first and treat them. I'd almost ignore EBV (not quite) until coinfections are dealt with. We know the big enemy is EBV but the coinfections will create havoc. Buhners use of herbs is interesting because he notes that some infections such as mycoplasmas and bartonellas have effexlor pumps that render some antibiotics useless and herbs can get through that barrier.
We also cant tell what is a permanent and what is a temporary effect of infection. Clearly the metabolism is altered. My preference is to aggressively boost the ability to make ATP while continuing to fight infection. That gives the body the best chance to solve some of the problems. I'll have a better look at Leonards note over the next few days.

Regards

[Leonard]

Anonymoose, perhaps your struggle "my labs and fluctuating well-being in non-ms ways indicate something not good was happening while I improved in other ways" is caused while you did not address it all at the same time. Perhaps your immune system left a vacuum for other infections to grow after you depleted all B-cells with Rituximab. And perhaps we should take a chemo like Methotrexate to kill off as many infections as possible together with Rituximab, as is the common practice in rheuma arthritis, a disease very similar to MS and with common roots.

I looked a bit deeper on Methotrexate. For sure it is an old medication where patents will have run out. So there is little money to be made for this medical pharmalogical complex. And therefore perhaps not of real interest to them; they will be more interested in pushing something else. And hence sidelined...
https://en.wikipedia.org/wiki/Methotrexate

Notwithstanding, it is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system. I think its application may be much broader than what is actually the case.

What I find interesting is that the mechanisms of action of Methotrexate for cancer and for rheuma look quite different. whow. what is this? is this all guess work? I think from this wiki description, it may be clear that no one can really look deep into our microcosm and fully understand what happens. And therefore my conceptual thinking in the lines below may be just as good as theirs.

I think that Methotrexate gets into the cells. From the wiki article, there is an effect on the Adenosine, in fact it causes an accumulation of the Adenosine!! Is this an indication that the cell machinery starts functioning better, after the MS and the oxidative stress took it down?

There is indication that those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes. Better endothelial function? Lower inflammation? Hence, by the same token, MS activity down?

My grandfarther died from a Naso Pharyngeal Carcinoma (NPC). Doctors were able to find back his record from more than 50 years ago (1963!). NPC is caused by EBV. I consider myself to have - although small - an above average risk. Would this be an other reason for using Methotrexate along side with Rituximab?

An advantage of Methotrexate over Mitoxantrone (I think Terry Wahls used for her remarkable recovery) is that the latter weighs heavily on the heart muscle. Apparently Methotrexate is a chemo that is better tolerated.

[Scott1]

Hi Leonard,

Now you're looking at this path, what is your daily protocol at the moment?

Regards

[Anonymoose]

Anonymoose, perhaps your struggle "my labs and fluctuating well-being in non-ms ways indicate something not good was happening while I improved in other ways" is caused while you did not address it all at the same time. Perhaps your immune system left a vacuum for other infections to grow after you depleted all B-cells with Rituximab. And perhaps we should take a chemo like Methotrexate to kill off as many infections as possible together with Rituximab, as is the common practice in rheuma arthritis, a disease very similar to MS and with common roots.

I looked a bit deeper on Methotrexate. For sure it is an old medication where patents will have run out. So there is little money to be made for this medical pharmalogical complex. And therefore perhaps not of real interest to them. And hence sidelined...
https://en.wikipedia.org/wiki/Methotrexate

What I find interesting is that the mechanisms of action of Methotrexate for cancer and for rheuma look quite different. whow. what is this? is this all guess work? I think from this wiki description, it may be clear that no one can really look deep into our microcosm and fully understand what happens. And therefore my conceptual thinking in the lines below may be just as good as theirs.

I think that Methotrexate gets into the cells. From the wiki article, there is an effect on the Adenosine, in fact it causes an accumulation of the Adenosine!! Is this an indication that the cell machinery starts functioning better, after the MS and the oxidative stress took it down?

There is indication that those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes. Better endothelial function? Lower inflammation? Hence, by the same token, MS activity down?

My grandfarther died from a Naso Pharyngeal Carcinoma (NPC). Doctors were able to find back his record from more than 50 years ago (1963!). NPC is caused by EBV. I consider myself to have an above average risk. Would this be an other reason for using Methotrexate along side with Rituximab?

An advantage of Methotrexate over Mitoxantrone (I think Terry Wahls used for her remarkable recovery) is that the latter weighs heavily on the heart muscle. Apparently Methotrexate is as a chemo that is better tolerated.

Methotrexate scares me. No matter what I read about it, my mind just screams NO! I might feel differently if I were more greatly affected by ms symptoms. I've yet to read anything that says methotrexate fights infections. Is that somewhere between the lines?

Do you have a doctor willing to manage you through rituxan and methotrexate and the aftermath? Mine was happy to administer the rituxan but then totally dropped the ball and left me to figure out everything on my own. You don't want to be in that position...which is why I am all for addressing co-infections first. You need to be as healthy as possible before you go for the big guns.