Theories: "Auto-Immune" vs. Not

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Theories: "Auto-Immune" vs. Not

Postby kareng7 » Thu Apr 28, 2005 4:04 pm

I'm a great lover of theories, especially when faced with a complex topic like MS where the first thing the medical community and published articles say is "no one knows what causes..."

So I want to hear from you about your theories, in this case, regarding the concept of auto-immunity.

Do you believe the human body can and will mistakenly attack itself, i.e., be auto-immune?

Or do you believe there is a trigger involved, perhaps a very clever one (pathogen like a virus or bacteria) that can even mimic the human body's own structures, and this is what the body attacks?

Please include any URLs or referenceable information that supports your theory.
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Postby BioDocFL » Fri Apr 29, 2005 11:10 am

Kareng7,

If you look back over the last 7 or so pages of the General Discussion, you'll see that we have discussed a lot of different theories. We are interested in new theories and new
information relative to old theories. We certainly would welcome any new thoughts you have.

Wesley
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Postby kareng7 » Fri Apr 29, 2005 7:24 pm

Thanks, Wesley. I'll definitely share mine. So, where do you stand on the concept of auto-immunity, if you don't mind me asking?
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Postby BioDocFL » Mon May 02, 2005 11:23 am

Kareng7,

Sorry I haven't responded until now. I got a new computer and ThisIsMS didn't seem to allow me to send any messages from it. My office computer seems to work though. I guess I can only have one email address registered.

As I understand it, everyone has some low levels of autoantibodies against different components (autoantigens) of cells. However, the immune system keeps this under control by tolerating low levels of the circulating autoantigens. If the levels rise for some reason, the immune system could react. It might be that viral or bacterial activity could lead to an increase in some antigens, including autoantigens. However, my theory is that chromosome damage leads to loss of control of some genes so that those genes can be overexpressed. Products (ex. enzymes) from those genes can then lead to imbalances in some cellular components. Those components can form or stabilize complexes that are normally not seen in great amounts. The immune system then reacts to that. This explanation doesn't depend on a specific genetic mutation (an 'MS gene') and it doesn't depend on an irregularity in the immune system, the immune system is simply reacting as it normally would. It is something in the targeted cells and tissues that is provoking the reaction, and it is not necessarily exogenous (i.e. not necessarily viral or bacterial).

We had a long discussion on it in the General Discussion > Polyamines topic from last fall. It is on page 5 or 6 of the General Discussion topics by now. Since I did all that posting, I've come across a good deal of other information that goes along with it but it gets into even more complexity to explain and I can't divulge it since we are waiting to hear on some grants. I am in cancer research but I am in a position to test my ideas if I get one of the cancer grants for which I have applied. There are parallels in cancer and autoimmunity if my theory is right, just a difference in whether the affected cells are poised to replicate (cancer) or has differentiated and would prefer to go into apoptosis when out of balance (autoimmunity). I should be hearing in the next few months on the grants.

Wesley
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Postby Shayk » Wed May 25, 2005 6:10 pm

Hi, I ’m definitely not in the "auto-immune camp".

The following description, with emphasis added, of a planned presentation at the upcoming Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting captures some of my thinking about “not auto-immune”.

Is MS a Neurodegenerative Disease? (by Bruce Trapp)

Multiple Sclerosis is a disease of the Central Nervous System that destroys myelin, oligodendrocytes, neurons and axons. It is among the most destructive diseases of the human brain. In the absence of cause for this devastating disease, research has historically focused on the most obvious pathological feature of MS brains - inflammatory demyelination of white matter. This presentation will summarize recent data that supports the concept that inflammation is a secondary response to an underlying CNS disease, which affects the survival of oligodendrocytes and/or neurons. The data originate from pathological analysis of post-mortem MS brains, magnetic resonance imaging studies and the natural history of the disease. From the pathological perspective, demyelination and inflammation have been spatially dissociated in the cerebral cortex of MS patients. This is quite striking in lesions that occupy both subcortical white matter and the cerebral cortex. Prineas and colleagues have recently identified areas of white matter in post-mortem MS brains which contain dying oligodendrocytes but no inflammtory cells. Both MRI and natural history studies identify inflammatory lesions and relapses as modulators, but relatively poor predictors of disease progression in MS patients. A major predictor of disease progression in MS patients is chronological age as most MS patients reach EDSS 4.0 at a similar age independent of disease course (relapsing-remitting vs primary progressive), age of onset and number of relapses. This supports the concept that MS is a primary neurodegenerative disease with a subpopulation of patients having degrees of secondary inflammatory white matter lesions.

Here’s a link to the CMSC Program Summary in its entirety.

Now, what I want to know is, does anyone know at what age most MS patients reach EDSS 4.0? Is it the same age for men and women? Is it an age when one or more hormones (testosterone, estrogen, progesterone, DHEA, Vitamin D3, etc.) typically decline?

Thanks!

Sharon :)
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Postby HarryZ » Wed May 25, 2005 8:46 pm

Shayk,

Shayk wrote:Hi, I ’m definitely not in the "auto-immune camp".


And neither am I!

That article that you quoted pretty well summarizes the new thinking that is taking place by some MS researchers. But its acceptance is very slow and not too many of the established, conservative MS docs will agree with it.

One only has to look at the main focus of the meds that are currently approved for MS and where the majority of the research is still concentrated...and that is the immune system. Research has been fixated on this area for decades and what have we got so far.....no known cause and certainly not even close to a cure. The docs continue to try and alter the MS patient's immune system in the hope of stopping the progression of the disease but it isn't working.

Something else is causing the initial problem.....but so far nobody has been able to determine just what.

Harry
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Postby finn » Thu May 26, 2005 12:42 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:10 pm, edited 1 time in total.
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Postby bromley » Thu May 26, 2005 3:04 am

Sharon,

Thanks for this article. Unfortunately, like you, I'm becoming very sceptical about the auto-immune theory. The CRAB drugs have not been shown to stop the progression of disability. Even drugs which pretty much stop exacerbations such as Campath (when used on SP patients) have had no effect on stopping the progression of the disease. The current thinking in many circles is that you have to get in quick and hard to stop exacerbations. It is hoped that this will preserve the myelin and myelin making cells and therefore prevent further damage to the underlying axons. Only time will tell if such an approach will have any impact on the progression of this disease (I hope it will and some posts on the Campath forum look promising).

If neuro-degeneration is the problem, then tackling exacerbations is going to have limited effect. Also re-myelination will have little effect if neuro-degeneration is the real problem.

The big question which the researchers need to answer is why neuro-degeneration is taking place. Neuro-degeneration is (I imagine) the problem in other CNS diseases such as Parkinsons, ALS, Alzeimers (sp?). However, I have never seen these diseases described as auto-immune.

Many researchers are now looking at neuro-protection rather than just treatments to alter the immune system. Recent advances in stem cell research may also offer hope for the future - to replace lost axons / neurons / myelin etc.

On the issue of EDSS 4 and age - I haven't seen this before. This disease usually occurs between 20 and 40, but I have read that many teenagers and younger children are diagnosed with MS. This appears to be a very variable disease, particulalry for those who start with the RR version. The disease for some sufferers progresses very rapidly, while others have a milder course. But I'd like to know how many people who have had the disease for 25 or 30 years are still walking without aids.

It's good that researchers are now looking at this disease as not necessarily an auto-immune disease and that the neuro-degenerative theory is being examined.

On the flipside much of the research done to date, and the treatments which have been developed, will have been a waste of time. As usual this vile disease always has the last laugh.

Bromley
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Postby HarryZ » Thu May 26, 2005 5:35 am

Ian,

On the flipside much of the research done to date, and the treatments which have been developed, will have been a waste of time. As usual this vile disease always has the last laugh.


An unintended waste of time, yes......but the money that has been made by the companies involved has been huge. With so much investment tied up on this line of thinking, it is going to be a formidable task for any researcher to convince those in this field to change direction. I hope it happens sooner rather than later but I won't hold my breath!

Harry
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Postby bromley » Thu May 26, 2005 7:18 am

Harry,

There is some hope. See the attached article from the US MS Society. A group of scientists / researchers who will be trialling possible therapies which the big companies aren't interested in (I assume because little money can be made). Things are changing (albeit slowly).

Ian

http://www.nationalmssociety.org/Research-2005May11.asp
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Postby HarryZ » Thu May 26, 2005 7:29 am

Ian,

Yes, I've been reading about CORE in the past week or so and that is very encouraging. I 'd like to ask a theoretical question...if someone in CORE ended up discovering something that looked very promising but was totally in the opposite direction of the current auto-immune thinking, would a drug company come forward and carry on the necessary funding for this discovery of ever getting possible MS FDA approval?

Harry
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Postby Sharon » Thu May 26, 2005 7:36 am

Bromley,

From your prior post:
But I'd like to know how many people who have had the disease for 25 or 30 years are still walking without aids


I am almost 62 years of age (darn!), was dx'd in 2003 but I strongly feel I could have been diagnosed at least 30 years ago. I work full time, golf on the weekend for relaxation (use a cart, I do not walk the course) and I do not use any aids for walking. I participated in a trial exercise program for MS patients in 2004 - my EDSS score was rated "3" by one doctor and "2" by another doctor. I continue with physical therapy to keep the muscles as strong as possible. When I get tired or stressed I walk with a limp - fortunately I am now at an age where many of my non-MS friends also walk with a limp (arthritis, sports injuries, etc.) so my limp goes unnoticed. :wink:

Let's hope the researches keep the "blinders" off, and continue to look at dynamics other than autoimmune. There are so many variables to this disease - maybe there is more than one solution.

The Other Sharon
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Postby raven » Thu May 26, 2005 9:14 am

I'm in the autoimmune camp..

Firstly the fact that a cause or cure for MS has not been found is not prima facia evidence that MS is not auto-immune. Alzheimers, Parkinsons, ALS, MND etc. also have no known cause or cure. This is not evidence that the research that has gone into these diseases is wrong. There is no cure for diabetes or arthritis, yet they are both accepted as auto-immune.

Whilst only partially effective, the available DMDs for MS do influence the course of the disease. Whilst long term data does not exist due to the relative youth of the treatments, early data supports a positive effect.

The main text that is quoted by those who argue against auto-immunity is that of Prineas and Barnett. The abstract of this paper is posted below

The study describes the clinical and pathological findings in 12 patients with relapsing and remitting multiple sclerosis, who died during or shortly after the onset of a relapse. Pathological changes not previously associated with the formation of new symptomatic lesions were observed in seven cases, namely, extensive oligodendrocyte apoptosis and microglial activation in myelinated tissue containing few or no lymphocytes or myelin phagocytes. No current laboratory model of multiple sclerosis, in particular, experimental allergic encephalomyelitis, is known with these features, which raises the possibility of some novel process underlying new lesion formation in multiple sclerosis.


In a reply to this paper it was noted that at least some of the subjects had been treated with high-dose cortico-steroids prior to death. This treatment may well have suppressed the signs of lymphocytes.

http://www3.interscience.wiley.com/cgi-bin/fulltext/109859436/HTMLSTART

Prineas and Barnett do note extensive microglial activation. It is noted in the following abstract that autoantibodies can activate the microglia without necessarily involving the lymphocytes

microglia were activated focally and phagocytosed the collapsed myelin. This study demonstrates that an antibody directed against myelin-forming cells induces CNS demyelination and supports the hypothesis that autoantibodies may play a role in CNS demyelinating diseases.


http://www3.interscience.wiley.com/cgi-bin/abstract/77191/ABSTRACT

The Maggs & Palace paper draws a lot of sources together to argue against auto-immunity. However the source material is carefully chosen and to a certain extent mis-represented. For example they quote the failure of Campath to arrest the progression of disability in SPMS patients as evidence against auto-immunity. They do not mention the RRMS patients that have shown extensive recovery after treatment. I myself am a recipient of Campath and am improving beyond my expectations (although I will be the first to admit that it's very early days for me)

The work of P. Behan argues that EAE is not a suitable model for MS. Most MS researchers would agree that EAE is not a perfect match but in the absence of a better model there is no alternative.

I'm not being critical, an open mind in any field of research is a good thing, alternatives should be considered. However to dismiss the huge body of work that exists that supports the auto-immune theory is equally blinkered.

As far as people reaching EDSS 4.0 at roughly the same age, this is something I have never heard of and is not supported by the people I know personally with MS. Perhaps we could have a poll? I'm 40 and was classified as EDSS 4.0 2 months ago.

Robin
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Postby DenverCO » Thu May 26, 2005 9:54 am

I recently attended a presentation by Dr. Allen Bowling titled "An Update on Current MS Research & Treatments". My take on what he said was that researchers are fairly convinced that multiple factors need to be present for an individual to get MS. An example MIGHT BE something like a viral trigger that only attacks people with a certain genetic profile.

Another speaker, a forensic pathologist from the Rocky Mountain MS Center brain bank, pointed out that MS has a distinct lesion pattern in the brain making it easy to distinguish from other demyelinating diseases, but they are more and more convinced that there are clearly different forms of the disease.

The gist of the whole thing? Figuring out the cause of MS is going to be even more difficult than previously thought. Wonderful.

IMO we need to continue with the inflammation focus, but researchers need to simultaneously explore the other theories.

As we all know, it all comes down to research dollars. With all of the complicated unknowns about MS, there will need to be billions more dollars poured into research; however MS is an "orphan disease". Not a large enough percentage of the population has the disease compared to other health problems (such as obesity and geriatric related maladies.) The FDA needs to realize that we are not a small group of quiet, helpless homebodies who have resigned ourselves to having an incurable disease.

Whatever your viewpoint is regarding Tysabri, it cannot be argued that it has created a very loud roar from the MS population that has gotten the attention of the FDA.
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Postby bromley » Thu May 26, 2005 10:41 am

DenverCo,

I think that we'll see a breakthrough with this disease in the not too distant future (3 years?). It's my first anniversary of my dx on Friday and even in a year there have been tremendous strides in other medical / health areas such as stem cell research and cancer research. Our time will come.

The MSIF site provides summaries of all the ms research papers that are published and there are often half a dozen papers a day. I just hope that someone is having an overview and making links between findings. The Boston Cure Project is seeking to identify the cause/s in a logical and systematic way.

Treatments such as Campath (for RR patients) and Tovaxin, where patients are seeing a stabilisation or improvement in their condition should enable scientists to identify the mechanisms behind such improvements.

We all know drugs companies are in for the money but they will be under pressure to identify more effective treatments rather than just rely on the 30% effective CRABs.

We all have our hunches on what might be behind this disease. EBV would be my bet (I saw a car today with EBV at the end of its registration plate!). There was an article in the UK newspapers last weekend about a young girl who had brain tumours caused by EBV. She was expected to die but they tried a new therapy - killer T cells which target the EBV virus. She made a dramatic recovery. If such a trigger was found for MS such therapies should be able to help.

This is all a bit off thread, but I'm in a more hopeful mood today (but not enough to use that annoying phrase 'there's never been a better time to have ms').


Ian
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