Autoimmunity is not just a theory in MS

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Re: Autoimmunity is not just a theory in MS

Postby shaight » Tue Jan 17, 2012 5:48 am

lyndacarol wrote:CVfactor – switching to baking soda may not be a bad idea. I think the sugar alcohol, sorbitol, in most toothpastes triggers the pancreas to produce extra…… insulin!


yes, and the xylitol they're adding these days can kill your dog! ...not that i'm brushing my dogs teeth :-D
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Tue Jan 17, 2012 9:29 am

To continue on with the accumulating evidence that MS may be caused by laten viruses that lie dormant in the body until re-activated, and that
regulatory Tcells play a role, here is a new recent discovery that ties into this:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569179/

We have identified at least 2 highly promiscuous major histocompatibility complex class II T-cell epitopes in the Fc fragment of IgG that are capable of specifically activating CD4+CD25HiFoxP3+ natural regulatory T cells (nTRegs). Coincubation of these regulatory T-cell epitopes or “Tregitopes” and antigens with peripheral blood mononuclear cells led to a suppression of effector cytokine secretion, reduced proliferation of effector T cells, and caused an increase in cell surface markers associated with TRegs such as FoxP3. In vivo administration of the murine homologue of the Fc region Tregitope resulted in suppression of immune response to a known immunogen. These data suggest that one mechanism for the immunosuppressive activity of IgG, such as with IVIG, may be related to the activity of regulatory T cells. In this model, regulatory T-cell epitopes in IgG activate a subset of nTRegs that tips the resulting immune response toward tolerance rather than immunogenicity.


To explain this a little more, in the immune system there are antibodies generated (called IgG or immunogobulin) that are developed by B-Cells which become
sensitized to antigens (fragments of a virus) and are used to neutralize the virus in the blood as well as activate T-cell to initiate an immune attack.

This is part of Humoral immunity and is one of the reasons why the immune system has "memory". For example, this is what prevents you from re-acquiring a cold once you have already recovered from it.

At any rate, within these antibodies there have been found what has been termed "Tregitopes" at the base (Fc region) of the Y shape antibody. It seems these Tregitopes activate regulatory T cells to shut-down immune responses when viral antigens have been cleared of a site of ongoing inflamation:

Image

When IgG and antigen (either complexed or separately) are internalized into the same APC (and TLR ligands or other “danger signals” are present), the response to effector epitopes may outnumber the Tregitopes, resulting in an initial inflammatory response. As antigen is cleared and the ratio of Ig to antigen increases, the balance tips toward tolerance, diminishing immune response and reducing further tissue damage and adverse systemic effects.


So, the theory is that you have effector T cells that are cross reactive to self epitopes as well as to the viral antigens. Normally when the virus is cleared, the ratio of viral antibodies to virus increases and the regulatory T-cells would be activated to shut down the immune response. But it seems that in people with MS, there are defects in these regulatory T cells (number or function), so autoimunity would occur.

Incidentally, there is a treatment for MS called IVIg, which a product that consists of antibodies obtained from thousands of individuals.

http://www.msadvances.com/faq.php3

It seems that introduction of this therapy has an effect on reducing disease but it was never known why.

Further studies need to be performed, but these Tregitopes may provide an explanation for the limited immunogenicity of Fc fusion proteins, the expansion of CD4+CD25Hi regulatory T cells after administration of therapeutic IVIG,8 and the observed effect of immunoglobulin therapy on autoimmune diseases and other medical conditions.
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Re: Autoimmunity is not just a theory in MS

Postby CureOrBust » Wed Jan 18, 2012 3:31 am

shaight wrote:yes, and the xylitol they're adding these days can kill your dog! ...not that i'm brushing my dogs teeth :-D
You should try and train them to rinse and spit the mouthwash!
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Re: Autoimmunity is not just a theory in MS

Postby jamesoeck » Wed Jan 18, 2012 7:53 am

Boy what a lot of information on this subject of Autoimmunity theory in Multiple Sclerosis. I have had it for over 30 yrs. and been in a wheelchair since 1989. I did not have all of these new drugs when I got my diagnosis that I have MS. I lost over 50% of my vision in my left eye. So I'm glad to see all of this science to come up with the right treatment for Multiple Sclerosis. I have found that it is different in a lot of my friends that have been diagnosis with MS. So that saying that it is different in each one makes it more difficult to come up with ONE treatment for everyone. I like what is being done in research on the T cell profile. The new drug that is on the market now that is a pill that you can take will only help certain patients that are still able to walk. So that is a big step forward but what about the patients that have problems with energy and need a wheelchair to be mobile. There is a lot of very good information on this site but wish that it could be made more public.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Wed Jan 18, 2012 10:09 am

jamesoeck,

I think that many researchers believe that the new drugs do indeed help some, but the efficacy is still not high enough to help all and is nowhere near a cure. But I feel that lack of effectiveness prompts researchers to understand why these drugs do not work and look futher into the mechanisms of MS.

Some people feel this is all a big conspiracy by neurologists and drug companies, but in my view you have to start somewhere. The mysteries of the immune system are only now being discovered and I think people working on the basic science of MS are close to understanding what causes MS. It is pretty clear now that this disease is caused by a loss of self tolerance and this also seems to be the case for many autoimune diseases. Similarly, this also is key in organ transplants because the immune system is not tolerance to these new tissues that are implanted. Researchers have just uncovered the mechanisms behind tolerance and a key seems to be the regulatory T cell. Here is a good video presentation regarding this by researchers working on Diabetes which is also an immune disese:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2565852/

So, in my view the way to restore tolerance right now is to eliminate the cells from the body that do not have this problem. HSCT stem cell transplant seems to be the best choice at the moment to halt disease progression.

Once this is established, the next step would be to repair damage that has already occurred. This also seems to be appropriate for some sort of stem cell therapy, but science is not there yet.
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Thu Jan 19, 2012 5:34 pm

Some EBV data points. . .

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

ttp://www.neurology.org/content/78/1/15.abstract

Study Offers Insight on How Epstein-Barr Virus May Play a Role in MS

http://www.nationalmssociety.org/news/n ... x?nid=5836
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Fri Jan 20, 2012 9:06 am

There is definitely a lot of investigation going on with Epstein-Barr. It seems this virus infects B-cells in most people and hides out in a dormant state until re-activated. This is where the problem comes in for people with MS who have developed an immune system through a combination of genetics and environment that inappropriately reacts to this virus, confusion self from non-self:

http://www.ncbi.nlm.nih.gov/pubmed/18432410

Epstein-Barr virus (EBV) is a human herpesvirus hiding in a latent form in memory B cells in the majority of the world population. Although, primary EBV infection is asymptomatic or causes a self-limiting disease, infectious mononucleosis, the virus is associated with a wide variety of neoplasms developing in immunosuppressed or immunodeficient individuals, but also in patients with an apparently intact immune system. In memory B cells, tumor cells, and lymphoblastoid cell lines (LCLs, transformed by EBV in vitro) the expression of the viral genes is highly restricted. There is no virus production (lytic viral replication associated with the expression of all viral genes) in tight latency. The expression of latent viral oncogenes and RNAs is under a strict epigenetic control via DNA methylation and histone modifications that results either in a complete silencing of the EBV genome in memory B cells, or in a cell-type dependent usage of latent promoters in tumor cells, germinal center B cells, and LCLs. Both the latent and lytic EBV proteins are potent immunogens and elicit vigorous B- and T-cell responses. In immunosuppressed and immunodeficient patients, or in individuals with a functional defect of EBV-specific T cells, lytic EBV replication is regularly activated and an increased viral load can be detected in the blood. Enhanced lytic replication results in new infection events and EBV-associated transformation events, and seems to be a risk factor both for malignant transformation and the development of autoimmune diseases. One may speculate that an increased load or altered presentation of a limited set of lytic or latent EBV proteins that cross-react with cellular antigens triggers and perpetuates the pathogenic processes that result in multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis. In addition, in SLE patients EBV may cause defects of B-cell tolerance checkpoints because latent membrane protein 1, an EBV-encoded viral oncoprotein can induce BAFF, a B-cell activating factor that rescues self-reactive B cells and induces a lupus-like autoimmune disease in transgenic mice.
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Fri Jan 20, 2012 9:24 am

That is truly interesting, CV. I had not known before that the main latent repository of EBV in the human body is primarily in the B-cells. It turns out that HSCT ablates/eliminates nearly all the B-cells, in addition to the T-cells. So if EBV does have some contributing factor to the development of MS, I can see how immunoablation might provide a curative effect.

Although clearly there is more to the story than just EBV since latent EBV infection is in the majority of the world population, but most people do not develop MS.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Fri Jan 20, 2012 9:56 am

Yes George, I think HSCT covers all bases which is why it has such a success rate.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Mon Jan 23, 2012 3:25 pm

More compelling evidence of the link with Epstein-Barr virus and multiple sclerosis:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089959/

Primary Infection with the Epstein-Barr Virus and Risk of Multiple Sclerosis

To determine whether multiple sclerosis (MS) risk increases following primary infection with the Epstein-Barr virus (EBV), we conducted a nested case-control study including 305 individuals who developed MS and 610 matched controls selected among the over 8 million active-duty military personnel with serum stored in the Department of Defense Serum Repository. Time of EBV infection was determined by measuring antibody titers in serial serum samples collected before MS onset among cases, and on matched dates among controls. Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative. . All of the 10 EBV-negative cases became EBV positive before MS onset ; in contrast, only 35.7 % (10) of the 28 controls with follow-up samples seroconverted (exact p value = 0.0008). We conclude that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Wed Jan 25, 2012 6:21 pm

Here is a new article on the unifying theory of MS:

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis
http://www.hindawi.com/journals/ad/2012/189096/
CD8+ T-cell deficiency is a general feature of chronic autoimmune diseases and also occurs in healthy blood relatives of patients with these diseases. It is proposed that this deficiency is genetically determined and underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of EBV infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells. Autoimmunity is postulated to evolve in a series of steps culminating in the development of ectopic lymphoid follicles containing EBV-infected autoreactive B cells in the target organ. It is also proposed that deprivation of sunlight and vitamin D facilitates the development of autoimmune diseases by aggravating the CD8+ T cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Thu Jan 26, 2012 10:21 am

CVfactor wrote:Here is a new article on the unifying theory of MS:

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis
http://www.hindawi.com/journals/ad/2012/189096/
CD8+ T-cell deficiency is a general feature of chronic autoimmune diseases and also occurs in healthy blood relatives of patients with these diseases. It is proposed that this deficiency is genetically determined and underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of EBV infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells. Autoimmunity is postulated to evolve in a series of steps culminating in the development of ectopic lymphoid follicles containing EBV-infected autoreactive B cells in the target organ. It is also proposed that deprivation of sunlight and vitamin D facilitates the development of autoimmune diseases by aggravating the CD8+ T cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.


Another fascinating post, CV. Just my mind wandering. . . . . If EBV does play a significant role in the development of MS (via costimulatory signals), I wonder why anti-viral drugs (such as Acyclovir and Gancyclovir that also work against EBV) don't appear to have any effect on the course of MS. Perhaps just too late like closing the barn door after the horse has left?

I do find the plausible theory of vitamin D deficiency as an aggravating factor associated with CD8+ diminution quite interesting. Seems to make sense to me since the CD4+ / CD8+ populations are important relative to self-tolerance.

Seems like the scientific understanding is making good strides toward finally understanding the underlying cause of MS. Almost seems that this could happen within our lifetime. And once this is known, it should be straighforward to know the most effective way to stop MS, or prevent it from even happening in the first place. Then we wouldn't need to resort to the "sledhammer" of HSCT to accomplish the same thing.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Thu Jan 26, 2012 3:35 pm

George, good question about antiviral drugs but Im not an expert in this area. My guess would be that they prevent manifestations of EBV such as mono but do not eliminate the virus itself.

Here is a article on a EBV vaccine that may be entering phase III trials:

http://www.medscape.com/viewarticle/753031
November 7, 2011 — An Epstein-Barr virus (EBV)
vaccine in the early phases of development may
prove able to prevent infectious mononucleosis and
EBV-associated cancers, without necessarily
preventing the EBV infection itself. The vaccine
targets the EBV glycoprotein gp350, which is the
most abundant glycoprotein on the virus and on
virus-infected cells.


So Im not sure you can eliminate the virus from the body totally, except with HSCT which would only be until you re-acquire the virus. But since you are also erasing the immune system biography your odds of getting MS would seem low to me.

I think science may be a long way from eliminating EBV from humans, but I think this would most likely prevent people from getting MS.

Personally I think that both EBV and vitamin D have a role. When I first was struck with ADEM I caught a "flu" from my nephew and after a few weeks the world came crashing down on me. I found out in the hospital that my vitamin D level was quite deficient. Maybe it is a coincidence or maybe I was one of those people who were exposed to EBV later in life.

Also my mother had Hoshimotos thyroiditis, so there is definetely something with genetics, environment and temporal exposure that sets this in motion from my point of view.
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Thu Jan 26, 2012 4:18 pm

CVfactor wrote:George, good question about antiviral drugs but Im not an expert in this area. My guess would be that they prevent manifestations of EBV such as mono but do not eliminate the virus itself.

Here is a article on a EBV vaccine that may be entering phase III trials:

http://www.medscape.com/viewarticle/753031
November 7, 2011 — An Epstein-Barr virus (EBV)
vaccine in the early phases of development may
prove able to prevent infectious mononucleosis and
EBV-associated cancers, without necessarily
preventing the EBV infection itself. The vaccine
targets the EBV glycoprotein gp350, which is the
most abundant glycoprotein on the virus and on
virus-infected cells.


So Im not sure you can eliminate the virus from the body totally, except with HSCT which would only be until you re-acquire the virus. But since you are also erasing the immune system biography your odds of getting MS would seem low to me.

I think science may be a long way from eliminating EBV from humans, but I think this would most likely prevent people from getting MS.

Personally I think that both EBV and vitamin D have a role. When I first was struck with ADEM I caught a "flu" from my nephew and after a few weeks the world came crashing down on me. I found out in the hospital that my vitamin D level was quite deficient. Maybe it is a coincidence or maybe I was one of those people who were exposed to EBV later in life.

Also my mother had Hoshimotos thyroiditis, so there is definetely something with genetics, environment and temporal exposure that sets this in motion from my point of view.


Hi CV. . . . sorry to hear about your ADEM. May I ask?. . . since ADEM is very similar in symptomatic manifestation to MS, how do you specifically know that its ADEM and not MS? What age were you diagnosed? Seems like ADEM is mostly diagnosed in a younger age bracket as compared to the (mostly) young adulthood (average around 30 years of age) with MS. And with ADEM there clearly is a strong and obvious correlation with a viral load from infections or live vaccinations, EBV being a major suspected culprit. So this also makes sense that there is so much potential similarity with MS. Did your ADEM go into remission, or are you part of the minority in which it became chronic and is still active?

Anyway. . . shedding light on either ADEM or MS will undoubtedly help in understanding the other. Perhaps even both maladys might share curative therapy.

Thanks in advance for forgiving my nosey questions.

George
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Thu Jan 26, 2012 5:28 pm

Hi George,

Yes I was struck with ADEM in 2009 when I was 40. The majority of victims are children, but it can effect people of any age. Usually the disease is monophasic in its course meaning that it strikes once and then leaves you alone if you have proper care. If you go to the hospital and they have good doctors they may be able to know what is wrong and put a stop to it with high dose intravenous steroids that will spare any permanent damage. If they dont understand what is going on and mistake it for viral encephalitis you could end up dying from this (10% estimated mortlity rate) or have permanent disability.

A certain percentage will have relapsing ADEM, and may eventually be re-diagnosed with MS down the road. So it is estimated that you have a 30% chance of acquiring MS. This seems to be where I am going because I have been having relapsing MS-like symptoms.

ADEM is rare (8/1,000,000) and acute but many researchers think this is part of a spectrum of diseases that include MS (there is a chart that shows this on the first page of this thread). So most likely if you know what causes MS you may be able to prevent all diseases in this spectrum.
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