Inflammation vs. neurodegeneration

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby HarryZ » Sat Mar 03, 2007 7:55 pm

Hi Finn,

Needless to say, I am very glad to see you back participating in the forum. Your posts have always been well written and objective. Welcome back.

Actually, according to the results of AFFIRM trial Tysabri wasn't able to slow down time to disability progression, but reduce the relative risk of disability progression by 42%. I bet you can see the difference between the nature of those statements. Anyway, I personally wouldn't put too much weight on that conclusion because the trial was done with patients in such a good shape. Over 71% of the placebo group (and 82% of the treated group) remained without any disease progression during the whole trial.


I bet you don't get a job interview with the Biogen marketing department :D

Harry
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Postby Lyon » Sat Mar 03, 2007 8:08 pm

ewizabeth wrote:What if there are not any signs of inflammation, but there is still progression. Is that generally the point which MS turns to a gradual decline even without the inflammation?
Hi ewizabeth,
I recently posted this link in another thread http://www.nationalmssociety.org/source ... gnosis.asp which might help you decide if your diseases is progressing into another course.

I'm not terribly familiar with what you ask but I will add that in viewing bromley's post earlier in this thread regarding results shown with the newer, much more powerful and discerning MRI machines as opposed results found and assumptions based on less powerful MRI machines, it seems reasonable to question how often progression without accompanying inflammation and lesions is accurate.

Bob
Last edited by Lyon on Sun Mar 11, 2007 4:42 pm, edited 1 time in total.
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Postby Manchester » Sun Mar 04, 2007 3:04 am

Excellent post Finn, I agree completely with you that MS is not an autoimmune condition. I too believe in applying Occam's razor to the majority of puzzles in life, however, I have not yet made my mind up if we are looking at a single pathogen cause or if MS is more syndrome, either way the underlying cause is not, in my opinion, autoimmune.


ewizabeth- MS progresses with or without relapse in all types of MS, even, in my opinion so called benign MS. Neuro-degeneration is probably present long before the first symptoms show and long before a person has a 'relapse'.

However, it may be that inflammation affords some level of protection and the question is getting the balance right between enough inflammation and too much inflammation, in MS usually there is too much inflammation and this also causes damage but this damage is separate from the underlying neuro-degeneration.

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Postby finn » Sun Mar 04, 2007 3:26 am

Lyon,
thanks for your long answer. Unfortunately, I have to say that the quality of information you provided to support your point of view was a disappointment to me. Where was the beef?

Researchers have found clusters where families suffer from more than one "autoimmune" disease, but does it necessarely mean that those families have something wrong with their immune system in the first place? I personally don't think so. Of course genetics (or epigenetics) more or less define our susceptibility to them, but there might be also other things in common with different "autoimmune" diseases.

Some researchers have already suggested that MS could be a "metabolic and hormonal disorder". If that's really the case, you could say the same about diabetes and some thyroid problems (maybe RA, too). On the other hand, in a recent study researchers were able to cure diabetes in mice by shutting down some faulty nerves. So maybe one day the "autoimmune" reaction in diabetes is found to be caused by damage in the nervous system, not vice versa. Who knows?

ewisabeth,
Manchester already wrote what I was planning to write :-)

Manchester,
I really appreciate your feedback. I've been reading your posts with great interest, too.

Harry,
thanks! You're probably right, maybe I should try Teva instead of Biogen ;-)

-finn
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Postby TwistedHelix » Sun Mar 04, 2007 8:50 am

Hey Finn,

I believe the piece of research you mentioned in your last paragraph about diabetes, was the discovery that the axons themselves triggered their own destruction by the release of neuropeptides, thus "calling in" the immune system rather than the system itself being at fault.
At the moment, it's a rather "chicken and egg "situation, (i e no-one's quite sure which came first), but it does look more and more likely that neurodegeneration is the underlying pathology, while plaque formation etc may be a secondary response which varies from person to person and which explains the variety in disease course. In a way, then, we all have PPMS!

Of course, this still leaves the question of what causes the degeneration in the first place. There is a large family of genes called CNP, ( cyclic nucleotide phosphodiesterases), some of which are expressed within oligodendrocytes. If this gene is missing or faulty the cells still produce myelin which looks absolutely normal, but inside, the axon degenerates chronically and amyloid precursor protein builds up. I don't know whether the same is true of grey matter neurons, but it looks as if there is a number of candidates for the position of "axon destroyer", as a primary, rather than secondary, component of MS,

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Postby finn » Sun Mar 04, 2007 10:12 am

Dom,
this is the study I referred to: "Type 1 diabetes has long been described as an autoimmune disease in which the body’s immune system targets islet cells in the pancreas, eventually destroying their ability to produce insulin. Without insulin, the body cannot convert glucose into energy, so people with type 1 diabetes have to regularly inject themselves with insulin to survive. However, what initiates the original attack on the pancreas had been unclear. It now seems that the nervous system may play a key role, according to researchers in Toronto, Canada. The team eliminated the disease in diabetes-prone mice by knocking out a set of faulty sensory nerves."

Naturally the relevance of the study depends on how closely the animal model of diabetes resembles the disease in humans. If they were as close to each other as EAE and MS, I wouldn't put too much weight on it :-)

Thanks for interesting post(s), and the CNP info.

TwistedHelix wrote:In a way, then, we all have PPMS!

Well put!

-finn
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Postby bromley » Sun Mar 04, 2007 10:21 am

Finn & co,

I don't think many of us consider that MS is a truly "auto-immune" disease. It's just that, until the pathogen is identified, it is a label that is used. No one calls PML (which resulted in the tragic deaths on the Tysabri trial) auto-immune, as the JC virus is considered the culprit.

I'm going to leave it to the researchers to figure out what comes first - inflammation or neuro-degeneration. But we do know that:

- inflammation plays a role in this disease.
- in addition to myelin, axons and neurons are damaged / destroyed.

PPMS is the fly in the ointment as inflamamtion appears to play much less of a role. And I, like you Finn, are surprised between the similarities in SPMS and PPMS where the disease is very much about neuro-degeneration and no immune-suppressing / anti-inflammatory treatments appear to make a jot of difference.

One of the best explanations / theories I heard from one of my MS neuros was that MS creates a toxic environment in the CNS. One of the consequences of this is damage / death to the myelin making cells which support axons. Perhaps it is the death / damage to these cells and the impact on the axons, which leads to their slow death? Identifying the initiator of the disease will be the key. My gut feeling is a virus and particularly EBV which resides in B cells for life once someone has been infected. Two pieces of research may well come up with the answer



Title: The study of T-cell responses to Epstein-Barr virus in multiple sclerosis.

Researchers: Dr Aleksandra Lenarczyk
Prof Michael Pender
Dr Scott Burrows

Neuroimmunology Research Centre, The University of Queensland

Summary and Progress (March 2006):

A large body of evidence suggests that infection with EBV, the causative agent of glandular fever, has a role in the cause of many chronic autoimmune diseases, including MS. Prof. M Pender has published a hypothesis proposing that MS occurs in individuals genetically susceptible to the effects of B cell (lymphocyte that make antibodies) infection by EBV; this results in an increased number of infected B cells capable of making antibodies against the brain and promoting the survival of another type of lymphocyte (T cell) which also attacks the brain (Pender M. Trends Immunol 2003; 24: 584). This project aims to test an important component of the hypothesis that explores the T cell responses against EBV in patients with MS. Our results so far indicate that MS patients have an increased level of EBV infection and decreased T-cell immunity to EBV. The significance of our studies is that they will shed light on the role of EBV in the development of MS and may lead to new and effective treatments for MS.


The role of Epstein-Barr virus (EBV) in triggering disease activity in MS
Category cause of MS
,
Institution University College London
Researcher Dr G. Giovannoni

It is generally accepted that genes play a role in determining who is at risk for developing MS. But an interaction with the environment rather then genes alone is suspected to confer susceptibility to developing MS. More then 20 infectious agents including measles, rubella, mumps and the herpes viruses, in particular the Epstein-Barr virus (EBV) have all been associated with MS at onset and/or relapses.

Although higher concentration of antibodies against each of these, have been detected in the serum and cerebrospinal fluid (CSF) of people with MS, their direct contribution to MS onset and progression remains unclear.

The Epstein-Barr virus, which causes glandular fever, like other herpes viruses, has the ability to lie dormant or latent in the body and to reactivate itself intermittently. These episodes of EBV reactivation generally do not cause symptoms in the general population. Latest research studies however suggest that in people with MS EBV reactivation may trigger relapses. The aim of this project is to investigate the link between EBV infection and MS disease activity, in particular the link between EBV reactivation and relapses. The hope is that if EBV infection and reactivation does have a role in MS disease onset and/or relapses future MS treatments targeting EBV could be developed.
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Postby ewizabeth » Sun Mar 04, 2007 10:30 am

You've all made me think a lot about my experiences with the disease modifying drugs.

Ian, when you wrote the following, it made me think that my most recent MRI may have been done with an older machine. There were no enhancing lesions, and nothing glaringly bad in regards to old damage, but I have gotten worse in the past few years in several ways. Almost like aging 30 years in three years.

Also, when I had my two IVSM treatments, they had an opposite effect on me, my walking degraded, I lost weight, and cognitive functions suffered as a result while on them and awhile later as well.

bromley wrote:My recent posting about the 8 Tesla scanner showed that there were many more lesions than could be seen with a conventional MRI scanner.

There was also some research about patients with progressive MS who were treated with very powerful immuno-suppressants. These patients still experienced atrophy / more disability despite the treatment...


Finn,

Thanks for that link. I'm sure that will help lots of us. :-) I had a stats class in college, but math is not my preferred subject...

finn wrote:BTW, there's an excellent article on understanding clinical trials in Accelerated Cure's newsletter (page 4).



Bob,

You make a good point, and hopefully some of the things we are doing are in the right direction. I hope it's soon that they figure out more pieces of the puzzle. And thanks for referring me to Ian's post. :-)

Lyon wrote:Upon asking, any reputable researcher will quickly admit that those things (increased permeability of the blood brain barrier, inflammation, myelin loss, lesions, axon loss and brain atrophy) are only the aspects of the MS process which have been identified to this point and might also point out that those are not necessarily the entirety of the MS process.


Manchester,

Thanks for explaining that. That makes me think about what I've gone through the past few years. I'm feeling worse, but the brain MRI is clear of enhancement. My white blood cell counts have been lower the past few years on the injectables. I'm trying to stay in the Tovaxin trial, where I need to have enough of the MRTC's for them to make the vaccine from my blood. My doctor thinks that my overall low WBC counts may disallow them to get enough of the MRTC's. Apparently higher WBC counts indicate inflammation (and more presence of T cells), and I haven't had this in the past few years, although progressing. What a puzzle.

Manchester wrote:ewizabeth- MS progresses with or without relapse in all types of MS, even, in my opinion so called benign MS. Neuro-degeneration is probably present long before the first symptoms show and long before a person has a 'relapse'.

However, it may be that inflammation affords some level of protection and the question is getting the balance right between enough inflammation and too much inflammation, in MS usually there is too much inflammation and this also causes damage but this damage is separate from the underlying neuro-degeneration.


Finn,

Thanks for all the good insight and references plus thought provoking conversation you brought to us with this. My family has several of the aforementioned diseases... and if not autoimmune, then what?

finn wrote:Researchers have found clusters where families suffer from more than one "autoimmune" disease, but does it necessarely mean that those families have something wrong with their immune system in the first place? I personally don't think so. Of course genetics (or epigenetics) more or less define our susceptibility to them, but there might be also other things in common with different "autoimmune" diseases.

Some researchers have already suggested that MS could be a "metabolic and hormonal disorder". If that's really the case, you could say the same about diabetes and some thyroid problems (maybe RA, too). On the other hand, in a recent study researchers were able to cure diabetes in mice by shutting down some faulty nerves. So maybe one day the "autoimmune" reaction in diabetes is found to be caused by damage in the nervous system, not vice versa. Who knows?

ewisabeth,
Manchester already wrote what I was planning to write :-)

Take care, Ewizabeth Previously Avonex, Rebif & Copaxone RRMS ~Tysabri, 31 infusions, ended 9/09. Starting Copaxone 12/09, waiting for Cladribine to be approved in 2010.
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Postby Lyon » Sun Mar 04, 2007 11:06 am

Hi ewizabeth,
You make a good point, and hopefully some of the things we are doing are in the right direction. I hope it's soon that they figure out more pieces of the puzzle. And thanks for referring me to Ian's post. Smile
I've said it many times before and I'm even more convinced now that MS is so complicated that we will see an acceptible resolution LONG before MS is understood and finessed to death.

Sure, the acceptible resolution might involve what might be considered a hack job like the sledgehammer approach of rebooting or the feather approach of Tovaxin but stopping the disease is what we're after. I don't ask that the method be pretty. Pretty and more refinement can come later.

There is no "good" time to have MS, but historically this is the best time. I'm convinced that this time in history will, in retrospect, be viewed as the beginning of the end for MS.

Bob
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Postby TwistedHelix » Sun Mar 04, 2007 1:07 pm

This is the link, (originally posted by NoBS), which suggests to me that nerves can create their OWN 'toxic environment', (by not releasing enough neuropeptide--my mistake):

http://www.cbc.ca/canada/calgary/story/2006/12/14/diabetes-neuron.html

Dom.[/i]
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Postby dignan » Sun Mar 04, 2007 6:10 pm

All very interesting stuff. To build on what Bromley posted earlier, I think this study (below) could add a significant piece of the puzzle. It seems to me at this point, the key roadblock isn't a lack of smart researchers looking in the right direction, but rather a lack of imaging techniques to prove or disprove many of the findings suggested by recent in vitro studies.



Imaging The Physiological Consequences Of Inflammation And Impulse Activity On Normal And Demyelinated CNS Axons

Institution: King’s College London
Researcher: Prof. Ken Smith
Amount funded: £194,049 -- Accepted for funding.

Axonal degeneration is a major cause of permanent disability in MS, but little is known about the underlying mechanisms and this hampers the goal of identifying rational therapies. Indirect evidence indicates that inflammation impairs mitochondrial metabolism and causes intra-axonal ion imbalance, but these important effects are not accessible to direct study using conventional morphological and electrophysiological techniques.

In pilot studies linking University and King’s Colleges, the research team have shown that it is now possible to apply confocal imaging techniques to examine the effects of experimental inflammatory and demyelinating lesions on the physiology of living axons and their glial cells in real time. They therefore propose to apply this novel and unique approach to understand how inflammatory cells and mediators affect neural tissue, with a focus on mechanisms that impair mitochondrial metabolism and cause ion imbalance in normal, demyelinated and remyelinating axons, and their ensheathing glial cells. In particular, they will explore the mechanisms underlying the finding that impulse activity in axons exposed to nitric oxide can cause axonal degeneration.

The research team have hypothesised that nitric oxide-mediated inhibition of mitochondria contributes to axonal sodium loading and thereby lethal calcium overload, through reverse activity of the sodium/calcium exchanger. The steps in this hypothesis can now be tested directly in live tissue, thereby not only illuminating mechanisms involved in axonal degeneration, but also potentially indicating novel strategies for axonal protection in inflammatory disorders of the nervous system.

http://www.mssociety.org.uk/research/re ... t_844.html
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Postby Shayk » Sun Mar 04, 2007 8:40 pm

Finn

Thanks so much for your excellent post. 8)

Dignan

I think it's all quite interesting too and I do think smart researchers are looking in the right direction as you said.

This reviewby people at Harvard notes:
Although several therapies exist for multiple sclerosis (MS), the most common inflammatory demyelinating disease of the central nervous system (CNS), there remains a large unmet clinical need for more effective immunomodulatory treatments in this category of diseases and for interventions that address their neurodegenerative component, which is currently untreated.

Preventing the entry of lymphocytes into the CNS and modifying the nature of the immune response are treatment approaches that work in the inflammatory component of MS but have little or no effect on neurodegeneration. Two challenges confront us: to develop cocktails of therapies that shift the immune homeostasis of patients with MS toward a healthy profile, and to identify and modulate the activity of targets within the neurodegenerative component of MS.

I definitely think the shift in focus to neuroprotection to prevent neurodegeneration is a shift in the right direction for people with MS and it's great that trials have already been initiated.

Sharon
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Postby finn » Mon Mar 05, 2007 6:40 am

Ian,
IMO the rapid change in the way we see the nature of MS is due to few innovative researchers, who have been brave enough to publish controversial papers. When I was diagnosed in year 2000, according to consensus opinion MS was definitely an autoimmune disease. And according to one of the ABCR-manufacturers "it was a good time to get diagnosed with MS, because now there was a way to effectively halt its progression with medication". Better treatments - maybe even a cure - were "just around the corner".

Two years later two controversial papers were published. One by Professor P.O.Behan and Senior Lecturer A.Chaudhuri questioned EAE as a animal model of MS, the use of current medication, and MS being an autoimmune disease. The other by Tsunoda and Fujonami showed that instead of developing from myelin loss to axonal degeneration (outside in), the disease process could start with axonal injury and then produce secondary damage, including demyelination (inside out). Both studies were silenced to death by the MS community. It took two more years before researchers were forced to start to openly discuss about the "no autoimmune" option. The reason for it was a well known pathologist John Prineas, who didn't find any signs of inflammation in the lesions of seven dead MS patients, but instead a large scale death of oligodendrocytes (myelin making cells).

Today it is widely accepted that lesion formation and damaged myelin alone can't explain the progression of permanent disability, and there's ongoing axonal degeneration present even in RRMS. Many researchers have already stopped calling MS an autoimmune disease. Like your neuro has stated, it may be true that the toxic environment in CNS could cause the death of oligodentrocytes, but why stop the speculation there? Maybe it starts by killing axons directly. In any case, we just need to know more about the cell biological processes in MS, and - most importantly - what happens outside lesions. After all, MS seems to be a "global disease of CNS".

IMO more important than to find out what causes it would be to know the primary disease process. That might be the only way to find ways to really halt (or even reverse) it.

dignan and Sharon,
Thanks for interesting posts.

Dom,
our links seem to refer to the same study :-)

Be well.

-finn
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Postby Loobie » Mon Mar 05, 2007 7:27 am

I'm going to show my ignorance here but I have a question that is entirely biased to my being in the Tovaxin trial and wanting it to be 'the one'. I can only read so much of the stuff that you guys have posted on this thread before my ADD and lack of knowledge about oligodendricytes and the like kicks in.

My question is this. It sounds to me that regardless of whether the "bad cells" are attacking myelin first or axons or whatever first, could it be assumed that the Tovaxin approach to neutralize the damaging cells has potential to work if either condition were present? After writing that sentence I realize that no one could really answer that definitively but I would like to hear an educated opinion from someone who can make it through that Dr. speak and also knows somewhat about the described mechanism of Tovaxin.

Thanks,
Lew
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Postby finn » Tue Mar 06, 2007 9:14 am

Lew,
Tovaxin is supposed to modulate the behaviour of certain type of immune cells. It is speculated that those cells are in responsible for damaging myelin. I have no idea if they were able to degenerate axons directly, but who knows, it might be possible.

In any case, good luck with the trial!

-finn
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