Autoimmunity is not just a theory in MS

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Autoimmunity is not just a theory in MS

Postby CVfactor » Fri Aug 12, 2011 8:01 pm

Since this seems like the only area on this site that openly talks about treatments for MS that rely on autoimmunity as the cause, I thought I would start a thread so that information can be presented in support of this.

I think this fits in with the heading of "stem cells" because this is the goal of treatments such as HSCT. The goal here is to restore immune tolerance and there is a great deal of research that supports this as the cause of MS as well as other autoimmune diseases.

To begin with, I have read a lot on this forum about how scientists have been working on the autoimmune theory for over a hundred years and it is time to look at other causes because they are not getting anywhere.

However, I think that the mechanisms of the immune system have only recently been started to be understood. Here is a good overview of the timeline of immunology:

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

So you can see that really T-cells have only been recognized since the decade of the 1970's. And in addition the latest breakthrough in the immune system is the discovery of regulatory T-cells in the last decade.

Here are two good presentations on this new discovery that gives more details about these cells and how they are trying to be manipulated to control the immune system:

http://www.youtube.com/watch?v=PYHvVj2qaDE

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

So it seems that the immune system is a balance between effector cells that protect against immunity and cancers as well as regulatory mechanism such as Tregs to prevent autoimmunity:

http://www.sciencedirect.com/science/article/pii/S0165572809001404

So I believe that the HSCT procedure restores tolerance by resetting the tolerance balance.

Here is a recent article that touches on this for people who underwent HSCT with donor stem cells for the treatment of leukemia:

http://www.jci.org/articles/view/41072

So, I think that rebooting the immune system is the best approach currently available for curing MS as well as other autoimmune diseases.

But I would like this approach be as successful for people with primary progressive MS as it is in RRMS, but there needs to be more research to understand why this is not the case. Here is a recent article that describes some of the issues that might be related to this in terms of thymic function:

http://bloodjournal.hematologylibrary.org/content/early/2011/03/22/blood-2011-02-334623.abstract

So I hope this thread can be used to provide new information from new discoveries in the treatment of all forms of MS.
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Postby georgegoss » Sat Aug 13, 2011 2:34 am

Thanks for posting this topic. It seems to me to be very valid, especially on the topic of stem cells.

I'm not sure if any of the following info would be considered "new" to anyone, but perhaps it dovetails with what you have already outlined. This is just copied from my blog posting:

And the science. . . .

It is still not understood "why" MS occurs. But it is well understood "what" is happening in individuals with MS.

As for the cause. . . The general prevailing (unconfirmed) belief among scientific professionals is that a genetically susceptible / vulnerable individual is exposed to a yet-to-be-identified environmental antagonist that initiates the neurologically-damaging immune self-intolerance of MS. I have heard the apt analogy that genetics loads the gun and the environment pulls the trigger. Clearly more elucidation is required in this area. However, here is some relevant scientifically-determined information from researchers at the University of California, Irvine pointing down this path:

Link Between Environment and Genetics in Triggering Multiple Sclerosis

http://www.sciencedaily.com/releases/20 ... 115313.htm

Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis

http://www.nature.com/ncomms/journal/v2 ... s1333.html

MS genetic discovery

http://www.ctv.ca/CTVNews/Health/201108 ... em-110811/

As for the underlying MS disease process / progression, the overwhelmingly-established science and scientifically-valid data clearly indicates that the mechanistic action of the underlying MS disease pathology is that of self-intolerant autoimmunity. Most doctors / researchers now consider this as fact, not just conjecture (as explained by these research scientists at Wayne State University):

Researchers publish results settling multiple sclerosis debate

http://media.wayne.edu/2011/02/22/wayne ... s-settling

"This work is significant because for the first time we are able to definitively establish a cause-and-effect relationship linking the marked T cells to the development of relapses and show unambiguously that it was the same T cells that mediated relapsing cycles"

"Targeting such disease-causing T-cells in MS is definitely a valid therapeutic approach that should be pursued," Tse added.


And indeed, this is exactly what HSCT does.

How & why does HSCT cure multiple sclerosis?

As a curative treatment HSCT works by changing the body's overall T- and B-lymphocyte epitope (antigen binding) repertoire, inactivating autoimmunity (making the body's immune cells "antigen naive") which results in restoration of immune self tolerance. This is often referred to as "resetting" the immune system which stops the underlying MS disease activity & progression. Once achieved, the body then has a chance to repair (or compensate for) some of the existing neural damage that is not undermined by further MS disease progression, often resulting in substantial and lasting symptomatic improvement.

The interesting fact here is that it is the chemotherapy which is effecting the curative aspect of the treatment by wiping out nearly all the long-lived T- and B-lymphocytes of the body that carry the faulty autoreactive memory so they may be replaced by naive, unprogrammed and self-tolerant non-autoreactive lymphocytes generated by the bone marrow. The stem cells themselves are not the specific reason for the curative effect of this treatment. The re-infusion of the hematopoietic stem cell autograft is simply for the purpose of re-establishing the bone marrow which has been ablated as part of the chemotherapy conditioning. So in effect, the stem cells are not curing the patient of MS, but are instead "rescuing" the patient from possible death as a result of the curative chemo conditioning regimen. This is why the stem cell graft is sometimes referred to as "stem cell rescue." It's just rescuing the patient from near certain death (for myeloablative protocols) due the treatment.

The takeaway concept here is no chemotherapy = no cure. This is why simply injecting stem cells into the body does not render the body's immune system self-tolerant as is required to stop the underlying MS disease activity.
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Postby CVfactor » Sun Aug 21, 2011 7:18 am

The evidence is becoming conclusive that MS is an autoimmune disease:

http://www.webmd.boots.com/news/20110812/new-genetic-clues-multiple-sclerosis

The genes identified in the new research include those that influence specific cells of the immune system, either through controlling interleukins (messenger chemicals that help immune cells communicate) or T-cells, which help the body fight off intruders. About a third of the genes identified are also linked to other autoimmune diseases, such as Crohn's disease, rheumatoid arthritis and type 1 diabetes.


And another new article:

http://www.nature.com/nature/journal/v476/n7359/full/nature10251.html

Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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Postby georgegoss » Sun Aug 21, 2011 11:41 am

CVfactor wrote:The evidence is becoming conclusive that MS is an autoimmune disease:

http://www.webmd.boots.com/news/20110812/new-genetic-clues-multiple-sclerosis

The genes identified in the new research include those that influence specific cells of the immune system, either through controlling interleukins (messenger chemicals that help immune cells communicate) or T-cells, which help the body fight off intruders. About a third of the genes identified are also linked to other autoimmune diseases, such as Crohn's disease, rheumatoid arthritis and type 1 diabetes.


And another new article:

http://www.nature.com/nature/journal/v476/n7359/full/nature10251.html

Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.


Great links & info. Just to throw a little more on top of it. . .

Researchers publish results settling multiple sclerosis debate

http://media.wayne.edu/2011/02/22/wayne ... s-settling

"This work is significant because for the first time we are able to definitively establish a cause-and-effect relationship linking the marked T cells to the development of relapses and show unambiguously that it was the same T cells that mediated relapsing cycles"

"Targeting such disease-causing T-cells in MS is definitely a valid therapeutic approach that should be pursued," Tse added.


And indeed, this is exactly what HSCT does.
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Postby CVfactor » Sun Aug 21, 2011 5:06 pm

George,

Yes, I read that article and it sheds a lot of light on the fact that the same T-cells were tracked during an attack which to me shows that epitope spreading could indeed be a factor in MS.

Incidentally, I see a neurologist who is a professor at the school of neurology at Wayne State University Medical School and is an expert on ADEM which is what I have. This disease is essentially EAE in humans. One day I went to the hospital with vomiting, fever, a headache and double vision. 30 days later I was released with an EDSS score of 7 in which I was totally imobile from the waist down.

About 1/3 of people with ADEM go on to have reacurrences and are eventually diagnosed with MS (which appears to be my case).

So, I my mind there is no question that MS is autoimune.

Which leads me to a new article about the "Biography" theory of MS, otherwise known as the "Darwinian Medicine" hypothesis:

http://www.hindawi.com/journals/ad/2011/708750/

Attention has recently focused on environmental factors associated with the increase in the incidence of several classes of disease in the industrially developed nations. The concept, forming the basis of the emerging discipline of “Darwinian medicine” [58], is that hygiene-related factors isolate the human population from micro-organisms, both pathogens and, probably more importantly, commensals, that are crucial to the establishment of beneficial immunoregulatory networks. Thus, in principle, an “interkingdom cross-talk” between microbes and the human host can establish patterns of immune reactivity that prevent various allergic, autoimmune, and inflammatory diseases while a failure of such cross-talk can facilitate them [59]. One consequence of improved hygiene is that certain infections that were previously regularly encountered in infancy now occur at a much later time in life and after other infections may have altered the patterns of immune responsiveness. Infection by EBV is a good example, and it has been postulated that various other infections acquired before EBV may affect immunoregulatory networks, thereby leading to an attrition or eclipse of those regulatory T cells (Tregs) that would otherwise protect against MS [10]. In this context, Tregs, though essential to immune function, may in some circumstances induce harmful effects and have therefore been termed a “dangerous necessity” [60].

Accordingly, a critical determinant of MS risk could be a compromised number or activity of protective Tregs [61, 62]. During an active and specific T cell-mediated immune response there could well be a competition with other kinds of T cells, most likely T-helper-cells, recognising the same epitope as the Tregs or epitopes closely spatially situated on the relevant antigen(s). As a consequence certain T-helper cell populations, that induce production of specific antibody, could become expanded and, thus, account for the diverse rise in antibody levels as epiphenomena with little or no pathologic importance. Notwithstanding, the local production of measles, varicella, or rubella-specific antibodies in the central nervous system can be useful for diagnosis [28–30], and the production of anti-HERV antibodies may become of use as prognostic factor for MS disease [4, 63].


To me, I think this theory explains a lot such as the influence of viruses (hygeine theory) on the development of the immune system. The Treg/Teffector cell balance seems to play a role and this "biolgraphy" of the immune system would explain why twins seem to have the same genetic make-up but different suseptability to acquiring MS. Also since Vitamin D also appears to promote the development of Tregs, I think the answer to the question is near.

Keep the research comming!
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Postby CVfactor » Sun Aug 28, 2011 5:04 pm

To expand a little more about the relationship of the "hygiene theory" and self tolerance, I would like to say a little bit more about the disease that brought me here.

Acute Disseminated Encephalomyelytis or ADEM is considered by the mainstream medical community as a MS spectrum disease. Below is a good graphic showing what this spectrum is:

Image

So, ADEM can be considered an acute form of MS and it is very similar to EAE in its disease course.

This is a very rare disease which strikes about 2000 people/year in the US. It is a monophasic disease in about 2/3 of the people who get it, meaning that it strikes once but will go away after proper medical care. The mortality rate is as high as 10%, and it usually strikes children but it can effect people of any age.

In the past, there were more cases because many of the early rabies vaccines contained brain matter protein that would encite an attack.

However, it is believed now that it follows a viral infection which was the case in my situation.

1/3 of people who acquire this disease are eventually re-diagnosed with MS which is also my situation.

So, from my point of view it seems that the cause of this disease is a case of a loss of self tolerance which is initiated by viral influences. This also seems to be what the mainstream medical community is finding also with MS.

To me, it appears that certain individuals may be more prone to losing self tolerance than other people (the genetic component), but they also have to undergo certain encounters with pathogens that trigger autoimmunity (Biography and Hygiene theories).

To me, this clearly explains why people who undergo the HSCT treatment have such a success rate (erasing the Biography of the immune system) as well as why some sets of identical twins don't always have the same propensity of acquiring MS (Hygeine theory).

So, the way to cure MS is to find the reason why some people lose self tolerance.

Here are some new review articles that look more closely at the science of MS:

http://www.hindawi.com/journals/ad/2011/si.1/
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Mon Dec 12, 2011 9:46 am

There is some chatter going on in the general discussion section about how MS also causes grey matter damage and that this somehow negates
the autoimune theory and supports the CCSVI theory.

However, in the mainstream medical communty the opposite is true. MS may indeed be two different diseases that are effected by different aspects of
the immune system such as cell mediated immunity (white matter inflamation) and humoral immuntiy (axonal damage).

So, it is clear that the major damage in the grey matter appears to be restricted to axonal damage. Futhermore, another componenet of MS seems to be damage to the optic nerve. So how would CCSVI explain this targeted destruction? I don't think it can.

Here is a article describing the pathology of nerve damage in the visual pathway:

http://brain.oxfordjournals.org/content/133/6/1575.short

And here is a new review of axonal damage in ms:
http://www.mendeley.com/research/axonal-damage-in-multiple-sclerosis-2/
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Fri Dec 23, 2011 5:31 pm

Here is an interesting new article that finds defects in the T cells produced in the thymus of both RRMS and PPMS:

http://www.hindawi.com/journals/msi/2011/461304/

Uncertainty exists as to whether similar or different mechanisms contribute to the pathogenesis of different subtypes of multiple sclerosis (MS). Detailed analysis of naive T cell homeostasis shows that patients with relapsing-remitting MS (RRMS) and with primary progressive MS (PPMS) have early-onset thymic involution that causes reduced thymic output. The reduced thymic output leads to secondary peripheral homeostatic alterations in naïve CD4 T-cells, which closely mimic T-cell alterations observed in an experimental animal model of diabetes mellitus. Homeostatic T-cell receptor (TCR) signalling and proliferation of naïve T cells are induced by self-peptides. Consequently, the findings of increased TCR signalling of naïve CD4 T-cells, without increased proliferation, in PPMS, and the increased homeostatic proliferation of naïve CD4 T-cells in RRMS favour the development of autoimmunity. Thus, it seems highly likely that peripheral T-cell alterations secondary to a thymic abnormality contribute to the pathogenesis of both MS subtypes.


In addition it appears that people who undergo autologus HSCT seem to have the T cell abnormalities restored to normal:

One study of immunoablation/autologous stem cell transplantation as a treatment of MS showed that the post transplant MS patients “rebooted” their immune system such that the thymus produced new T cells having a diverse TCR repertoire [36 ].


This along with the fact that it has been proven that PWMS have abnormal regulatory T cells provides ample evidence why MS is autoimmune in nature.
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Sun Dec 25, 2011 12:30 pm

In addition it appears that people who undergo autologus HSCT seem to have the T cell abnormalities restored to normal.


This is a great article, CV. It does indeed add more explantation as to not only why MS is autoimmune in nature, but also why the majority of progressive-MS patient cases respond favorably to HSCT (wiping out the majority of in-vivo T-cell population).

Just another curiousity that I find very interesting that may, or may not be somehow related to the curative effect of HSCT on MS. . . . . normally people have a greater CD4+/CD8+ cellular population. However, following HSCT that ablates most of the existing T-cell population, the body initially produces an imbalance of these cell sub-types as replacements in which the CD4+/CD8+ cell type populations become inverted, and remain that way for years (because theese cells are so long-lived). This cellular imbalance is innocuous, but still not understood why it happens. Two years past my own transplantation my cell subtypes are still inverted to this day. Probably will remain this way until four or five years out. It doesn't cause a problem, but I still find it interesting.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Mon Dec 26, 2011 6:14 pm

George,

That is interesting about what happens to the T cell balance after HSCT. From what I have read the CD4 T cells are more of a manager type of cell that recruits other cells in immune responses. The CD8 cell is a cell that actually performs the immune respone (one of many types) which is why it is known as a cytotoxic T cell. So in MS lesions you will find CD8 cells but not many CD4 cells (with the exception of at the active edges of the lesion).

But there are many subclasses of these cells such as memory and regulatory.

Below is a pretty good description from Wikipedia which seems to sum up what is known about these cells:

http://en.m.wikipedia.org/wiki/T_cell


It would be interesting to know how the T cell subclass distribution changes over time after HSCT, but I guess this is a subject for future research.
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Thu Dec 29, 2011 1:55 pm

T-cell sub-type population recovery following HSCT has been studied rather throroughly from the large population of treated cancer patients. I once saw a paper that detailed in graphical form the various sub-type populations over time. I will look for the paper (I may have it somewhere on my computer) and then post a link to it.

For now, here is a Mayo clinic paper on the general subject claiming that the CD4+/CD8+ ratio may remain inverted from normal for up to ten years post-transplantation. I personally find this effect quite interesting (even though it's not harmful):

Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation

http://www.mayoclinicproceedings.com/co ... 7.full.pdf

And another related article from the journal Blood:

Immune Reconstitution and Immunotherapy After Autologous Hematopoietic Stem Cell Transplantation

http://bloodjournal.hematologylibrary.o ... /1471.full
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Mon Jan 02, 2012 5:54 pm

George, I think that the CD4+/CD8+ balance may be reversed because CD4+ t cells come out of the thymus as naive cells and then are activated by antigen presenting cells as they are encountered (MHC II) molecules. CD8+ t cells may be already antigen specific to MHC class I antigens but are not yet activated. So, maybe it takes longer for CD4+ T cells to accumulate in their diversity as they encounter antigen presenting cells. This is my guess.

It seems that the CD4+ t cells are reset to the naive state and have no memory after HSCT. Here is a good article on this as it relates to polyspecific CD4+ T cells that are found in people with MS:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854652/
In keeping with the observation that specific T cells that have been primed by pathogens and cross-react with self antigens can cause autoimmunity in animal models, patients with autoimmune diseases such as SLE, rheumatoid arthritis and multiple sclerosis have been found to have higher frequencies and activation states and/or less co-stimulatory requirements of self-reactive lymphocytes 27-30. In multiple sclerosis, receptor analysis of T and B cells in CNS tissue and in the cerebrospinal fluid (CSF) showed clonal expansions in both populations, indicating that there is clonal reactivity to a restricted number of disease-relevant antigens 31-33. In addition, longitudinal studies provided evidence for long-term persistence of individual myelin-specific T-cell clones tracked over several years in the blood of patients with multiple sclerosis 34-36, indicating a strong, persisting memory response and/or ongoing autoantigen exposure at least for a subset of myelin-reactive T cells in multiple sclerosis.
We suggest that these memory responses reflect, at least in part, persisting clonal expansions of polyspecific T cells recognizing both self and virus antigens that have been found associated with human autoimmune diseases. For example, high viral loads that occur during symptomatic primary EBV infection, resulting in infectious mononucleosis, are associated with an increased risk of developing multiple sclerosis 37-39, and could prime these polyspecific T-cell responses.


So, it appears that MS may be caused by cross-reacting CD4+ T cells that are primed by viruses such as Ebstein-Barr. Also, it is not just one antigen/auto antigen that would be implicated in MS, but can be a variety due to the concept of epitope spreading:

In addition to autoimmune responses that are initially primed by APCs and stimulated by bystander activation, additional autoantigen-specific T or B cells can be primed through epitope spreading 45 — a situation in which an immune response that is initiated by various stimuli, including microbial infection, trauma, transplanted tissue or autoimmunity, ‘spreads’ to include responses directed against a different portion of the same protein (intramolecular spreading) or a different protein (intermolecular spreading). Activating a broader set of T cells through epitope spreading is helpful in an antipathogen or antitumour immune response, because the pathogen or tumour cannot easily escape immune control with a single mutation in an immunogenic epitope. However, disease potentially arises when spread to and within self proteins occurs subsequent to the destruction of self tissue.
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Mon Jan 02, 2012 6:13 pm

CVfactor wrote:George, I think that the CD4+/CD8+ balance may be reversed because CD4+ t cells come out of the thymus as naive cells and then are activated by antigen presenting cells as they are encountered (MHC II) molecules. CD8+ t cells may be already antigen specific to MHC class I antigens but are not yet activated. So, maybe it takes longer for CD4+ T cells to accumulate in their diversity as they encounter antigen presenting cells. This is my guess.

Sound like as good of an explanation as I've heard. You still have a future as an immunologist if you decide to go that route! :-)
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Wed Jan 04, 2012 9:57 am

georgegoss wrote:
CVfactor wrote:George, I think that the CD4+/CD8+ balance may be reversed because CD4+ t cells come out of the thymus as naive cells and then are activated by antigen presenting cells as they are encountered (MHC II) molecules. CD8+ t cells may be already antigen specific to MHC class I antigens but are not yet activated. So, maybe it takes longer for CD4+ T cells to accumulate in their diversity as they encounter antigen presenting cells. This is my guess.

Sound like as good of an explanation as I've heard. You still have a future as an immunologist if you decide to go that route! :-)


George, I'm not an immunologist but I do play one on the internet. :wink:

But I'm curious to know if with the non-myeloablative protocal do you also see a reversal of the CD4+/CD8+ T cell profile?
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Wed Jan 04, 2012 10:25 am

CVfactor wrote:But I'm curious to know if with the non-myeloablative protocal do you also see a reversal of the CD4+/CD8+ T cell profile?

An truly excellent question! I don't know the answer and haven't seen any specific data on this. Probably there is not much because the non-myeloablative protocol for MS has not treated anywhere near the number of patients as opposed to cancer patients that have undergone myeloabltive protocols (hundreds vs. millions). But I would be almost certain Dr. Burt knows the answer to this but I haven't seen him publish any data in this area.
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