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NHE
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Re: Anyone have a link for this article about Vitamin D?

Post by NHE »

zanne10000 wrote:I just saw my naturopath today and she said she went to an infectious disease conference recently and someone presented a study about Vitamin D, MS and a triggering infection (often EBV). I think the following info from the April 19th issue of Neurology is the article to which she's referring, but it costs $20 to access it. Does anyone have a free link to it? BTW, she has increased my Vit D to 40,000 IUs for 28 weeks based on what she heard at the conference. It's a high dose, I realize, but she said it was shown to be as effective as immune modulators. Thanks!



In Focus Robert A. Gross
Spotlight on the April 19 Issue Neurology April 19, 2011 76:1367

...data for diagnoses of multiple sclerosis (MS) and infectious mononucleosis were analyzed...provides support for interactions between vitamin D and Epstein-Barr virus in determining the prevalence of MS, which should be taken into account for...
If you have a university near you, then take a flash drive and head off to their research library. At my local university, I can save the pdf's to a flash drive and then print them out at home.

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Post by CVfactor »

To expand a little more on the concept of molecular mimicry, this is in essence the possibility that fragments of a virus (peptide) have a similar structure to that of autoantigens (fragments of your tissue such as Myelin Basic Protein).

Here is a good example showing this:

Image

You can see that in picture C, a E-coli peptide is structurally similar to a Myelin Basic Protein peptide.

And here is a good overview from Wikipedia on the Molecular Mimicry theory:

http://en.wikipedia.org/wiki/Molecular_mimicry

So basically your immune system T-cells could attack its own tissues because it believes it is a foreign antigen. This is known as cross-reactivity.

So as many may know, MS is more prevalent in women. Here is a paper that looks at cross-reactivity in male and female mice in EAE:

http://www.ncbi.nlm.nih.gov/pubmed/20950867

The conclusions are that female mice have a higher propensity for cross-reactivity than male mice.

But this goes back to there is increasing evidence that in healthy individuals, regulatory T-cells should be able to differentiate self from non-self.
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Re: Tr1 Regulatory Cells and Vitamin D

Post by NHE »

Thank you for posting the interesting image discussing the peptide structures and how this might influence molecular mimicry. In addition to physical structure, the chemistry of the various amino acid residues is also important when considering antibody and/or receptor cross reactivity. There are several residues where the chemistry is markedly different between the two peptides and I suspect that these differences might influence how the immune system responds to them. For example, ARG to VAL is a polar/basic to hydrophobic substitution, SER to LYS is a polar/neutral to polar/basic substitution, ALA to ASN is a nonpolar to polar substitution and HIS to VAL is a polar/acidic to nonpolar substitution. As you're likely aware, such substitutions, especially polar to nonpolar, will affect the three dimensional structure of the peptide in aqueous media thereby affecting antibody and receptor recognition. Not having read the full paper, I do not know if the authors address these differences though they are important when considering the homology of two different structures.

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Post by CVfactor »

NHE,

Yes, I think molecular mimicry can have many aspects of mechanism. It sounds like you are more familiar with the intricacies than I am.

But I found another very interesting article about T-cells and multiple sclerosis:

<shortened url>

This article is very good in my opinion because it goes into great detail about all of the different types of T-cells and their function.

Here is a good summary of what the authors believe about T-cells and MS:

"The importance of T-cells in the pathophysiology of MS is suggested by several
lines of evidence. T-cells are located at the active edge of MS lesions, and the presence
of perivascular infiltrates of T-cells throughout the CNS is a consistent feature
in all stages of the disease (Prineas 1975). Patients with MS have a higher frequency
of activated T-cells in their peripheral blood, specifically a higher percentage of
activated myelin-reactive T-cells (Hafler et al. 1985; Zhang et al. 1994). The strongest
genetic risk allele for the development of MS is in the class II HLA-DR locus, and
recently another risk allele has been identified in the class I HLA locus (Yeo et al.
2007), suggesting that antigen presentation to CD4+ and CD8+ T-cells plays a causal
role in the development of disease. In the EAE model, adoptive transfer of myelinreactive
T-cells into the peripheral blood of a previously healthy animal is sufficient
to transfer disease (Zamvil et al. 1985). Together, these findings have led to the
hypothesis that MS is a T-cell-mediated autoimmune disease.
Advances in our understanding of T-cell physiology have expanded our understanding
of their role in MS pathophysiology. It is becoming increasingly clear that
T-cells are not a monomorphic population differing only in their T-cell receptor
(TCR) specificities, but rather they are a diverse mix of proinflammatory and antiinflammatory
subtypes, whose reciprocal interactions we are just beginning to
understand. In this chapter, we review what is known about the specificity and functional
state of T-cells in MS patients. To understand more fully the physiology of
these cells, we examine the factors that enhance or inhibit T-cell activation and the
effector profiles T-cells assume after they are activated. We explore in detail the
regulatory role certain T-cells play in inhibiting autoimmune and other inflammatory
processes and the functional deficiency of these cells in MS. Finally, we discuss how
T-cells specifically affect, and are affected by, the local environment of the CNS."

And here is what the authors conclude about Tr1 regulatory cells and vitamin D:

"Unlike FoxP3+ Treg, Tr1 lineage fate is not determined in the thymus, but rather
Tr1 cells are induced from naïve cells by activation in the setting of the appropriate
conditioning signals. Several stimuli have been shown to result in the induction of
Tr1 cells in vitro. Activating T-cells with CD3/CD28 crosslinking in the presence
of IL-10 and IFNa, or with the combination of dexamethasone and 1-,25-(OH)2
Vitamin D3, both result in Tr1 induction (Levings et al. 2001; Barrat et al. 2002).
The latter combination has been of interest as low levels of Vitamin D have been
identified as an environmental risk factor for MS (Munger et al. 2004). Tr1 cells
can also be induced by crosslinking CD3 with the alternative costimulatory
receptor CD46 (Kemper et al. 2003). Finally, the combination of IL-27 and TGFb
also induces Tr1 cells, and this combination is thought to be the mechanism
through which FoxP3+ Treg modified dendritic cells induce Tr1 formation
(Awasthi et al. 2007)."

So, I believe from my own experience Vitamin D is definitely helping me with my disease. But of course this is only anecdotal. I would think future Vitamin D research on patients with MS is a promising approach to investigate.
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Pregnancy and Vitamin D may protect against MS - studies

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Image

Tasmanian researchers have found that delaying pregnancy may increase the likelihood of women getting multiple sclerosis.

A yet to be published study looking at MS over the last 60 years has found the frequency of the disease has risen dramatically and it's largely been driven by women.

The Menzies Research Institute's Associate Professor, Bruce Taylor, says delaying pregnancy could be having an impact.

"We think that having children is protective for having MS, He said.... Read More - http://www.msrc.co.uk/index.cfm/fuseact ... ageid/1936
MS-UK - http://www.ms-uk.org/
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Post by Leonard »

Hallo America, wake up! Start to think wider, more conceptual, don't get lost or trapped in technical details of MS lesions, in biological processes in areas where things have already gone terribly wrong.

What is the common factor of pregnancy and Vitamin D: exactly, the micro-cellular feeding is improved. The whole pregnancy is about nothing else than micro-cellular feeding. The Vitamin D enhances the grips of the insulin on the cells and thereby improved the micro-cellular feeding. Both have anti-inflammatory properties? Of course not, they improve the feeding of the cells and the neuro signalling pathways calm down.

In this same context, this is interesting:

In 1949, Dr. Hench first applied steriods for a purpose other than the substitution in people who have a deficiency of this hormone creation. She gave it to patients with polyarthritis, with good results. In fact they had seen that women who are pregnant and have rheumatism problems, during pregnancy usually have less or no rheumatism.

On the other hand it was known that during pregnancy the adrenal glands produce more cortisol. Dr. Hench found that the arthritis may have been suppressed by increased cortisol production and that proved right. Gradually it was discovered that cortisone has strong anti-inflammatory properties and the knowledge about steroids and their action was developed further...

From this time onwards, the anti-inflammatory aspects have been seen. I guess also by the neurologists who's discipline started to develop around more or less the same timeframe.

But is this true? Is this conceptually correct? Perhaps, it is the other way around. Perhaps this is not anti-inflammation by suppression but neuro-signalling pathways that calm down because of better nutrition of the cells. Most certainly, if seen in the context of a pregnancy which is all about feeding of the unborn child, or if seen from a more conceptual point of view, this much morelikely to do with enhanced feeding of the cells.

If you look at it like this, so many things just fit together so neatly...
see also http://www.thisisms.com/ftopic-15188-da ... c-150.html
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Post by CVfactor »

The article in the previous posts explains a lot about T-Cells and I think I will summarize it as follows:

1. It appears that MS is a T-cell mediated disease. In particular, helper T-cells otherwise known as Th cells (specifically the pro inflamitory helper T-cells Th1 and Th17).

2. Helper T-cells do not directly interact with tissues, but they recruit other cells such as macrophages and neutrophils to perform the actual cell destruction found in MS lesions via cytokines (chemical signals).

This is why T-cells are found surrounding the lesion at its surface but are rarely found within the lesion (in contrasts macrophages and neutrophils are found in the lesion).

3. It appears that helper t-cells are self reactive when they are developed in the thymus because they are not exposed to all auto-antigens during development. This is true of healthy individuals also.

4. It is the job of regulatory T-cells (Tregs) to prevent these helper T-cells from initiating a response against tissues in the central nervous system.

5. It seems that regulatory T-cells in people with MS are defective in providing this protection.

Here is another article that explains this in more detail:

http://www.sciencedirect.com/science/ar ... 1410000043

6. It seems that there is another variant of regulatory T-cells that can be developed that are separate from the naturally occurring regulatory T-cells which can prevent an auto-immune response by helper T-cells. These are known as induced or adaptive regulatory T-cells (iTreg, aTreg).

7. There is mounting evidence that Vitamin D (a steroid hormone) appears to promote the development of regulatory T-cell function.
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Vitamin D levels low in African-Americans with MS

Post by MSUK »

Image

African-Americans who have multiple sclerosis (MS) have lower vitamin D levels than African-Americans who don't have the disease, according to a study published in the May 24, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology. However, most of the difference in vitamin D levels was due to differences in climate and geography.

"MS is not as common in African-Americans as it is in whites, although the disease tends to be more severe in African-Americans," said study author Ari J. Green, MD, of the University of California San Francisco and a member of the American Academy of Neurology. "We have known that vitamin D levels are associated with MS and that African-Americans are at increased risk for having low vitamin D levels, but little research has been done to look at vitamin D levels in African-Americans with MS."... Read More - http://www.msrc.co.uk/index.cfm/fuseact ... ageid/1334
MS-UK - http://www.ms-uk.org/
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Post by CVfactor »

It appears that there is a lot of research now being conducted on regulatory T cells in areas where self tolerance is defficient (autoimmune diseases and allergy) as well as when tolerance needs to be induced (transplant rejection).

Here is a recent Podcast with Professor Robert Lechler, King's College London who is working on regulatory T-cells therapies to prevent transplant rejection, but also describes how these cells are crucial in the prevention of autoimmune diseases such as MS and Rheumatoid Arthritis:

http://nakeddiscovery.com/downloads/spl ... 2_8516.mp3
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Post by CVfactor »

Here is an article that was published in Scientific America about regulatory T-cells. It describes how they are believed to control many different autoimmune diseases:

http://www.smccd.net/accounts/digennaro ... -cells.pdf
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Post by CVfactor »

Here is a review article about regulatory T-cells and their function in autoimune diseases from The New England Journal of Medicine:

http://www.oncoinmun.cl/pdf2008/ihq2008/1166.pdf
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Post by CVfactor »

As shown in this thread, many researchers investigating autoimmune diseases are finding that the Treg function of people with these diseases are defective.

Here is another paper by researchers investigating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) which is a disease similar to MS that effects the meylin sheath in the periphery (not the CNS).

http://www.ncbi.nlm.nih.gov/pubmed/19886739

Conclusion is that Tregs are defective in people with CIDP compared with healthy controls.
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Post by CVfactor »

To explain a little more about vitamin D and its connection to regulatory T cells, I would first like to summarize some facts about Vitamin D.

1. Vitamin D is not a vitamin. It is a steroid hormone. You cannot get natural amounts of vitamin D from foods. For example, a healthy person in mid-day summer sun can synthesis 10,000 IU's of vitamin D in 1 hour. Compare this to the amount that is fortified in a glass of milk which is about 200 IU's.

2. There are three stages to vitamin D synthesis in the body. The first is called Cholecalciferol which is generated by UV exposure. This is the same as Vitamin D3 that you can purchase at any drug store.

Cholecalciferol is then hydroxylated in the liver to become calcifediol (25-hydroxyvitamin D3, otherwise known as Calcidiol). This is the main circulating form in your blood and is what should be checked by your doctor.

Finally, calcifediol is again hydroxylated, this time in the kidney but also by immune cells, and becomes calcitriol (1,25-dihydroxyvitamin D3). Calcitriol is the most active hormone form of vitamin D3.


3. There is mounting evidence that Vitamin D3 has a direct effect on regulatory T-cells. These Treg-cells restrain the immune system to prevent autoimune diseases and maintain self tolerance.

It appears from the mounting evidence that Tregs are defective in their supressive function in people with MS as well as other autoimune diseases.

I believe this is why there is such great success with the HSCT procedure, because it wipes out these defective Tregs and enables normal Tregs to perform their proper function in people with auto-immune diseases.

The key thing to remember is that all people generate self-reactive immune cells, but it appears that people with autoimmune diseases lack the function to shut-down an autoimmune response because of the lack of suppressing ability of their Tregs.

Here is a recent article that describes this:

http://www.ima.org.il/imaj/ar10mar-11.pdf

So to me, it is a no brainer to follow the recent studies of high doses of vitamin D (Phase I/II) on people with MS. I cannot understand why the MS community is not pushing for more research on vitamin D to find the optimum levels. There has been suspicion of a connection of vitamin D's role in preventing MS for more than 30 years, but little has been done to investigate this.
Last edited by CVfactor on Mon Jul 11, 2011 2:29 pm, edited 1 time in total.
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Re: Vitamin D3

Post by NHE »

Here's some more info on Vitamin D3.

Relapse frequency has been found to correlate inversely with vitamin D3 levels. 50-60 ng/mL (125-150 nmol/L) is a good target range. Note, the conversion factor for 25(OH) vitamin D3 ng/mL -> nmol/L = 2.496

http://www.thisisms.com/forum/post128403.html#p128403
higher 25-OH-D levels were associated with a reduced hazard of relapse. This occurred in a dose-dependent linear fashion, with each 10nmol/l increase in 25-OH-D resulting in up to a 12% reduction in risk of relapse. Clinically, raising 25-OH-D levels by 50nmol/l could halve the hazard of a relapse.
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