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uprightdoc wrote:These statements won't fly with neurologists or radiologists and they are so full of errors and controversy that I don't know where to start. Among other things, although there is a great degree of variability, MS has characteristic signs and symptoms clearly recognized by neurologists and radiologists. More importantly, the signs and symptoms commonly seen in MS aren't necessarily associated with the location of the lesions.

Righteous Doc :>)

You are right. Something I likely wrote at 3am in response to a message from Nigel without any thought is probably "so full of errors and controversy" that it isn't worth responding to! This was just one message out of many in a long conversation and not something I put together to be carefully scrutinized.

Not to defend my views, but to put all this in context, let me explain my hypothesis which I see as neither gospel nor science just something that makes sense to me.

Prof Hayes at U Wis has recently published a study which shows that she can cure EAE in 100% of her mice and keep it in remission in 100% of her mice with a single, high dose of calcitriol followed by daily, moderate doses of vitamin D3.

Her explanation for why this works if I am correctly understanding it, is that in EAE and likely MS, something has blocked the ability of cells to convert 25(OH)D3 to calcitriol, the bioactive form of vitamin D which if available would cause programmed cell death in CD4+ T-cells, particularly Th1 cells which are effectively immortal without calcitriol.

It goes beyond just CD4+ T-cells because without the ability to make calcitriol, there may well be other pro-inflammatory actors and anti-inflammatory actors which are not functioning properly in the CNS.

CD4+ Th1 cells have an affinity for myelin so may be the main cause of dymyelination in MS. Prof Hayes has focused on these as a key factor in EAE and MS based on years of research and this is what she measures to determine the effectiveness of the treatment.

A single, quite high dose of calcitriol effectively halts the disease by making calcitriol directly available to CD4+ Th1 cells which die off very quickly. This has the effect of essentially restarting the immune system. Pro-inflammatory cytokines are down regulated and anti-inflammatory cytokines upregulated. She doesn't explicitly say that calcitriol restarts the immune system. That is my characterization of it based on the fact that after administration of calcitriol, the cells are then able to convert D3 to calcitriol and pro-inflammatory cytokines disappear and anti-inflammatory ones increase.

My overview is a gross over simplification of something Prof Hayes has been studying for 25 years and running tests on in EAE mice for at least the past 10 years, but I think it is essentially correct in terms of what happens.

This raises the question of whether a single high dose of calcitriol + ongoing administration of vitD3 will have the same effect in pwMS.

Unlike mice, people are quite varied genetically. EAE is mimic of MS and likely differs with it in many critical ways, one of the most important being what sets off the disease in mice compared with what actually happens in humans.

That begs the question of what is MS and what is the initial trigger?

Grossly oversimplifying this and perhaps totally wrong because I do not fully understand it, I proposed that MS is a disease characterized by a break down in the blood brain barrier in which demyelination occurs, at least in part because CD4+ T-cells have an affinity for myelin which they tag for destruction by the CNS immune system. They don't belong on the CNS side of the BBB and they get there because it has been breached.

I think it is not unfair to say that a breach in the BBB and demyelination are two common characteristics of MS and possibly the only two that are true with everyone having MS. And I am the first to say I could be totally wrong here. There is certainly hypoxia. Some people may have a pathogenic infection. Almost all likely have venous malformation. But to have MS, I propose that you have to have a breach in the BBB and that myelin has to be damaged.

What I like about this simple view is that it allows for almost all the theories of what causes MS if it is viewed as starting initially with the breach of the BBB.

That could be caused by a viral, bacterial, fungal or protozoan pathogen. Or it could be caused by turbulent blood flow stemming from CCSVI. It could also be caused by injury or problems that cause turbulence in blood flow which is damaging to the endothelium.

I am fully aware that there is no agreement on what causes MS and that many theories have been offered. The only one that makes no sense to me and as far as I can see is unproven in spite of having been around for decades is that immune system for no reason goes haywire and begins attacking myelin.

I like the simplicity of this view of MS and the fact that it accounts for the variety of clinical symptoms of the disease. What happens individual by individual will likely depend on where the BBB is being injured. What is causing that injury and what further damage it can do if things that shouldn't cross the BBB into the CNS, do.

Bringing this back to whether calcitriol + D3 will work in humans as well as it has in mice is the question of whether the same process is at work, ie, are the cells in the CNS, particularly those involved in the inflammatory response which appears to be relatively immortal in MS, unable to convert D3 to calcitriol?

And what causes that?

A number of recent studies in Alzheimer's, IBD, cholangiocarcinoma, and other diseases have suggested that what happens is a proliferation of pro-inflammatory cytokines, particularly TNF-alpha and IL-6, blocks the operation of the CYP27B1 gene or in some way disrupt the process it initiates. This blocks the conversion of 25(OH)D3 to calcitriol which cells do when they are unable to obtain calcitriol from the blood.

Prof Hayes' approach of providing a single high dose of calcitriol bypasses this problem by making calcitriol directly available to the cells needing it.

If this works in psMS, we will have a way to manage the disease which supports, rather than suppresses the immune system, and does this with a single dose of an inexpensive, FDA-approved pharmaceutical (albeit off label because it isn't approved in MS or at these doses) and $35 worth of D3 every year.

Regardless of whether my interpretation and theories about the science that underlies this are correct, I think it is something that should be tested in humans ASAP.

It does not fix things like an EBV or CPn infection. It won't correct spinal misalignment if that is what is causing damage to the BBB, nor will it fix CCSVI venous malformations and blood flow. Nor will it work as a silver bullet that allows people to eat crappy food, not exercise and so on. It is a piece of the puzzle, not the whole solution.

It may be that this is just a short term fix and it will be necessary to take a high dose of calcitriol periodically to maintain the effect since unlike EAE, the original cause of the problem in MS has not gone away without treatment. But how bad would that be compared with what we are doing today.

Hack away at this. I have a very thick skin and am happy to learn something by being shown the error of my ways. :>)

Ed

Hi Ed,

I think think your view is a good one, what i want to add is that the auto immune hypothesis, from 1960, is blinding the medical sector.
That the immune system is disfunctioning has never been proven....

The lesions, demyelisation etc can have several causes, they only want to see one.....

Rgds,

Robert

Robnl wrote:. . . auto immune hypothesis, from 1960, is blinding the medical sector.
That the immune system is dysfunctioning has never been proven....

Robert,
In a sense, it is not wrong if what Hayes has found is correct.

Vitamin D which is a hormone both activates the adaptive immune system and stops activity when the job is done.

But something in the disease process and/or the immune response shuts down the ability to convert vitD 3 to calcitriol so there is no control over the immune response, the immune cells have in essence, become immortal.

So in this sense, the theory that the immune system is out of control and doing things that are harmful is in fact correct.

What I find so exciting about Prof Hayes' study is that if this works in pwMS, then it will be possible to treat MS by aiding the immune system rather than suppressing elements of it which is the main approach of the DMDs. Although this doesn't tell us what will happen in people, Hayes compared calcitriol + D3 against several commonly used DMDs in EAE mice and it certainly was superior:




Prof Hayes focused largely on how a high dose of calcitriol lowers certain types of CD4+ T-cells and promotes an increase in one that modulate the inflammatory response. Several recent studies point to TNF-a and IL-6 as the immune system cytokines that block the operation of CYP27B1 which is the gene that controls conversion of 25(OH)D3 to calcitriol. In her studies, these two cytokines must also be downregulated because after the calcitriol dose, conversion works again.

The question that comes to mind about Vit D and calcitriol is regarding which form of the hormone is the one that actually is the one that the body requires for the expression?

If Vit D is always converted by either liver or cells into calcitriol then the end form is the one to focus on.

The next thought moves to the effect that pathogen have on the immune system. They down regulate the immune system so in essence the calcitriol is required to cause apoptosis to the cells that have intracellular infections and B and T cells are known targets of diseases such as Lyme and or its co-infections.

So inflammation anywhere has to be considered as infection driven whether it is an injury as first 'cause' or other reasons. So the first to arrive and collect are actually infected cells even though they are the immune cells!

The cascades that occur are a combination of the good and the bad cellular activity.

So the cells that cross the BBB and tag myelin are often infected immune cells that are modified by pathogens and technically not self driven auto-immune cells.

An extrapolation would be that an under or over active immune system is a warning that there is pathogens intra-cellularly involved!

Good interview regarding this;

NZer1 wrote:The question that comes to mind about Vit D and calcitriol is regarding which form of the hormone is the one that actually is the one that the body requires for the expression?

Nigel,
The only form that is active is calcitriol, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3].

25(OH)D3 is a storage form that circulates in the blood to be available to cells for conversion, or the kidneys for conversion when serum levels of calcitriol are low.

NZer1 wrote:The next thought moves to the effect that pathogen have on the immune system. They down regulate the immune system so in essence the calcitriol is required to cause apoptosis to the cells that have intracellular infections and B and T cells are known targets of diseases such as Lyme and or its co-infections.

So inflammation anywhere has to be considered as infection driven whether it is an injury as first 'cause' or other reasons. So the first to arrive and collect are actually infected cells even though they are the immune cells!

The cascades that occur are a combination of the good and the bad cellular activity.

So the cells that cross the BBB and tag myelin are often infected immune cells that are modified by pathogens and technically not self driven auto-immune cells.

Nigel,
From what I can see in the literature, the infection of immune cells is a hypothesis, not something that is proven at this point.

I don't think anyone has established that "the cells that cross the BBB and tag myelin are often infected . . ."

That's not to say that this hypothesis isn't true, only that it is not proven to be true. If it is true, this would be an important difference between how calcitriol + D3 works in humans compared with EAE mice who have neither Lyme nor CPn infections.

What is being proven at some level is that TNFα and IL-6 which are known to be upregulated in MS have the effect of preventing the conversion of 25(OH)D3 to calcitriol by blocking the CYP27B1 pathway.

NZer1 wrote:So inflammation anywhere has to be considered as infection driven whether it is an injury as first 'cause' or other reasons. So the first to arrive and collect are actually infected cells even though they are the immune cells!

Nigel,
We don't know that. It may have been proposed as a theory, but I am not aware of any testing of this that establishes that this is in fact true in MS.

Ed,

I have several points of contention with the comments you posted previously. For one, EAE is not a good model for MS and mice are not good models for humans. This means that the study is based on a faulty premise. In my opinion, only about one-third of the MS patients I have consulted with have clear signs of autoimmune-inflammatory conditions or encephalitis. Most cases are related to malformations and structural injuries. The other major point I have is with the theory regarding breach of the BBB as a trigger for MS that allows viruses, bacteria, fungi, protozoa and other pathogens to cross into the brain and initiate an immune-inflammatory reaction. In this regard the BBB is breached all the time during normal physiology without consequence. Standing upright for example causes and increase in the permeability of the BBB. Increased CO2 levels also increase the permeability of the BBB as do certain anesthetics. The third point of contention is that it is assumed that breaches continue to occur where lesions are found but this hasn't been proven. Lesions are due to different causes and each cause affects permeability differently. For example, inflammation, edema and scar tissue affect permeability of the BBB in different ways that increase of decrease permeability. As you mentioned, trauma can also damage the BBB due to tension and shear stresses. Enlargement of the ventricles (ventriculomegaly) stretches the BBB which can increase its permeability. Increased permeability, however, isn't necessarily associated with an increase in signs, symptoms or pathology. I do agree that the calcitriol protocol proposal is fairly benign and should be studied. I suspect it is probably works primarily as an antiinflammatory agent. Nearly all MS patients have inflamation so it can't hurt to try.

Maybe the 'Medical community' will hear us talking and have a look at something that hasn't crossed their minds invoking a study or been seen as an income earner before?

When cells live within cells they seem to be out of sight and out of mind of the Medical community!


Nigel

uprightdoc wrote:Ed,

I have several points of contention with the comments you posted previously. For one, EAE is not a good model for MS and mice are not good models for humans. This means that the study is based on a faulty premise. In my opinion, only about one-third of the MS patients I have consulted with have clear signs of autoimmune-inflammatory conditions or encephalitis. Most cases are related to malformations and structural injuries. The other major point I have is with the theory regarding breach of the BBB as a trigger for MS that allows viruses, bacteria, fungi, protozoa and other pathogens to cross into the brain and initiate an immune-inflammatory reaction. In this regard the BBB is breached all the time during normal physiology without consequence. Standing upright for example causes and increase in the permeability of the BBB. Increased CO2 levels also increase the permeability of the BBB as do certain anesthetics. The third point of contention is that it is assumed that breaches continue to occur where lesions are found but this hasn't been proven. Lesions are due to different causes and each cause affects permeability differently. For example, inflammation, edema and scar tissue affect permeability of the BBB in different ways that increase of decrease permeability. As you mentioned, trauma can also damage the BBB due to tension and shear stresses. Enlargement of the ventricles (ventriculomegaly) stretches the BBB which can increase its permeability. Increased permeability, however, isn't necessarily associated with an increase in signs, symptoms or pathology. I do agree that the calcitriol protocol proposal is fairly benign and should be studied. I suspect it is probably works primarily as an antiinflammatory agent. Nearly all MS patients have inflamation so it can't hurt to try.

Dr F I think the key point we are all hovering around is whether the breach of the BBB is the 'main' reason that 'MS' occurs.

Many, many people have a dx of 'MS' and that is a dx of exclusion, so that can mean as you say you find people have other issues that confuse the dx process or are mimics of 'MS' and as soon as either of these scenarios occur the dx of 'MS' is removed.

So my main focus on 'MS' is to define what it is so that it can be dx-ed accurately.

There needs to be reason to give the dx that isn't challenged and that is why I asked others such as Franz Schelling is the finding of Dawsons Fingers or periventricular lesions the deciding factor.

As Ed pointed out to me the MRI findings of lesions, white spots, hyperintensities are indications of inflammation and not de-myelination so we need a focus point for the 'real' dx of 'MS'. Too many of us have ongoing progression that is related to the disability that is accumulating rather than than the core action that causes 'MS', imo.

Because research has 'said' that the immune system is dysregulated, some say up and others say down, then the immune system needs to be checked for issues such as Prof Hayes has found and as Ed is pushing for more human testing, calcitriol plays a major part, a huge part and that is also indicated in Vit D studies but misses the end product, the form that does the work rather than a pre-cursor!!

Define, define and define again to get to the core of the problem!


Nigel

At this point as Ed and I have laboured we are seeing the dx of 'MS' only occurs at Autopsy, lets change that!!


Nigel

uprightdoc wrote:Ed,

I have several points of contention with the comments you posted previously. For one, EAE is not a good model for MS and mice are not good models for humans. This means that the study is based on a faulty premise.

Doc,

Any model is imperfect, but we can't study disease in humans and terminate their lives to examine brain tissue so we need animal models as a starting point.

There are a number of obvious reasons that things we learn in models won't work in humans. I think the biggest of these is that lab mice are very homogeneous genetically compared to the far greater variation in humans.

In the case of the Hayes study, the relevant genes exist in humans and mice and there are similar levels of the same immune components found in both.

But the more important point to me is that what Hayes has shown in mice should be tested in humans to see if we get the same results. Calcitriol is an approved pharmaceutical and D3 is available over the counter. The risks involved in high dose calcitriol are known and manageable and the benefits if this works in humans almost immeasurable providing a quite good risk-benefit proposition.

uprightdoc wrote:The other major point I have is with the theory regarding breach of the BBB as a trigger for MS that allows viruses, bacteria, fungi, protozoa and other pathogens to cross into the brain and initiate an immune-inflammatory reaction.

My understanding is that the conventional view of MS is that it begins with a breach of the BBB and that is the way EAE is induced. I think my understanding of that is correct, even if that view is not.

The immune response is to the breach, or at least the initial immune response is to the breach.

That response is directed by the hormonal action of vitamin D which controls both angiogenesis and repair of injury to veins by activating the adaptive immune response and setting off the cell replacement which it controls.

I won't argue that the breach allows viruses, bacteria, fungi, protozoa to cross the BBB, I just tossed that in to keep Nigel happy. :>)

But if there is injury which allows things to pass into the CNS, I suppose they could and that would cause additional problems as would the passage of blood components such as RBCs.

Anything that isn't supposed to be on the CNS side will provoke a CNS immune response and may cause problems.

My understanding of Hayes is that one of the things crossing over is CD4+ T-cells which have an affinity for myelin and tag it as if it were foreign and in need of removal. While this may not be the only cause of demyelination, it is one that has been identified and in EAE mice given calcitriol + D3, those CD4+ T-cells undergo programmed cell death which is what stops the progression in EAE.

Because the immune response to the breach is pro-inflammatory and itself shuts down conversion of 25(OH)D3 to calcitriol, those CD4+ cells as well as other parts of the local adaptive immune response are immortal, there is insufficient calcitriol to trigger apoptosis. This means that even if the breach is successfully repaired as it must be, there is still the problem of rogue immune system cells in a highly inflammatory state.

In Hayes' EAE study where she directly measures the CD4 cells pre- and post-treatment, she can see that there is a rapid decline in the number of pro-inflammatory cells and an equally fast increase in the anti-inflammatory ones.

uprightdoc wrote:In this regard the BBB is breached all the time during normal physiology without consequence. Standing upright for example causes and increase in the permeability of the BBB. Increased CO2 levels also increase the permeability of the BBB as do certain anesthetics.

Doc,
All true, but physiological increases in permeability are not the same as "breaches" or bleeds, are they? Maybe "breach" is the wrong word, but I understood the essence of periventicular and perivenous lesions in MS and the whole process of inducing EAE in mice was to create a gap in the BBB, not just increase permeability.

uprightdoc wrote:The third point of contention is that it is assumed that breaches continue to occur where lesions are found but this hasn't been proven. Lesions are due to different causes and each cause affects permeability differently. For example, inflammation, edema and scar tissue affect permeability of the BBB in different ways that increase of decrease permeability. As you mentioned, trauma can also damage the BBB due to tension and shear stresses. Enlargement of the ventricles (ventriculomegaly) stretches the BBB which can increase its permeability. Increased permeability, however, isn't necessarily associated with an increase in signs, symptoms or pathology.

Doc,
It is obvious that the location of lesions changes over time on MRIs so I'm not sure anyone is arguing that they continue to occur, at least in the same spot.

But if there is injury to the endothelium, there will be an immune response to that injury. If that response shuts down the conversion of D3 to calcitriol, then the immune actors marshaled for that response are immortal, they are no longer being controlled by regulatory hormone vitamin D.

If this is true, then the injury may be repaired, but the inflammatory immune response continues and can't be stopped because the cells are unable to make calcitriol and there is not enough circulating in the blood in people who are Vitamin D deficient.

While it is only EAE, Hayes' experiments show that providing a high dose of calcitriol, high enough to ensure that there is plenty of it available in the brain and spinal cord is enough to halt that ongoing immune response which has continued after the problem that initiated it has passed.

Pure conjecture, but is it possible that RRMS is a phase in which there is ongoing breaks in the BBB and very active immune responses and PPMS is what happens after the breaks themselves are repaired, but there is continued immune activity, some of which is causing injury to myelin?