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HarryZ said:

I'm afraid I just can't agree with your logic on this. Again,the immune system of a MS patient is doing exactly what it was designed to do...detect and go after the problem...in the case of MS patients, this is inflammation around the myelin. Having MS doesn't, in my opinion, doesn't make any difference at all in this mechanism.

Well stated. This is the puzzle, is the immune system guilty from the start, or has it been lured into reacting to something abnormal going on in the CNS?

Wesley

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I think it is better to say MS has autoimmune involvement, rather than to say MS is an autoimmune disease. The later implies (to me at least) that the autoimmune reaction is the cause of MS. It might be the cause, it might be a consequence, and/or it might be a consequence that leads to further neuro damage. When we use the term 'autoimmune' it implies the immune system is attacking 'self' material. But the details of 'self' are vague. 'Self' might be an endogenous protein with the correct amino acids but there might be alterred modifications, like hypo- or hyper-acetylation. 'Self' might be endogenous DNA but it might have alterred methylation patterns or be stabilized in an alternate conformation like Z-DNA.
To say that something is an autoimmune disease can be a possible simplification of the situation. For example, in lupus, a majority of patients have auto-antibodies against DNA. As a matter of fact, everyone has some low level of auto-antibodies to DNA. DNA is usually in the B (righthanded coiling) state. Only transiently is it in the Z (lefthanded coiling) state. These different conformational states have tremendous impact on the supercoiling stress in chromatin and the accessibility of the genes. Now what I have read is that auto-antibodies in lupus are targeting mostly if not exclusively endogenous DNA. One of the big differences in lupus vs controls is that the anti-DNA antibodies seem to target potential Z-DNA forming sequences (G-C rich). There is also an enrichment of Alu sequences (very G-C rich) in the sera of lupus patients, suggesting something going on with those sequences. So, it would seem to me that, yes the immune system is targeting the person’s own DNA sequences but are they in the normal conformation or is there an inordinate increase in some usually less frequent conformation that is potentially a problem to the person? It would seem that Z-DNA stabilized by cations could be less digestable during apoptosis and therefore linger around longer as debris. Polyamines can stabilize Z-DNA and are elevated in lupus. So, yes in autoimmune diseases the immune system is attacking ‘self’. However, ‘self’ could be the right sequence of DNA or protein, but the ‘self’ could be in an altered conformation that appears abnormal to the immune system. Abnormal protein and DNA modifications, such as altered methylation or lack of methylation, could also give a different appearance to a large molecule that is otherwise ‘self’. I think I mentioned Alu RNA near the ribosome before. If a reverse transcriptase were to become active, translated by the ribosome, the first things it would latch on to for reverse transcription would probably be Alu RNA. These are rich in G-C and would normally be heavily methylated if in their normal context in the genes. But these Alu RNA transcripts and the resulting Alu DNA are not in their normal context and so there is great difficulty for the cell to methylate them (requiring de novo methylation rather than hemimethylation, if any methylation can occur at all on them). So these Alu DNA sequences of 80-410 bp being hypomethylated and in large quantity from the reverse transcription would appear to be foreign DNA to the body even though a molecular biologist would tell you that the Alu DNA sequences are endogenous.
Okay, that’s just one example from my main interest, lupus. What might be an example from MS? Myelin is considered a primary autoimmune target in MS. But could there be an initial provocation by some abnormal myelin that then becomes a general attack against most myelin by epitope spreading? I think an article was posted before about a California research group finding some examples where myelin near lesions had an increased positive charge. I don’t remember what they thought might be involved but it could be something like hypoacetylation of lysines or incorporation of some more positively charged small molecules in non-covalent associations. So when we say MS is an autoimmune disease that targets myelin, was the immune response triggered by something abnormal about myelin at a few sites that escalated into something broader and persistent due again to epitope-spreading?
Again, the puzzle of MS and other so-called autoimmune diseases, what initiates the problem? I rushed writing this. I hope it's clear what I'm saying but I probably won't be able to follow up. I've got to get back to work.

Wesley

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Wesley,

Your post is clear and very informative.

Thanks for taking the time to explain the autoimmune component so well.

gwa

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Bob,

Although only study and trial results which can't be considered "fact" at this point, it's hard not to consider the results of the Campath 1h, High Dose Cyclophosphamide and Tovaxin studies and trials in which depleting the T cells, in varying degrees, showed profound results. Admittedly results are short term at this point but the years are adding up and from what I can tell, continue to be favorable.

We know that one's immune system, in an attempt to go after the inflammation, causes more damage to the myelin. The CRAB drugs and Tysabri make an attempt to dampen this effect. Some MS patients benefit a bit and others get nothing. Very powerful immune system altering drugs like Cyclophosphamide and Campath shake a person's immune system to the core, severely curtail T-cell activity and thus will have some effect on the patient's MS....and the side-effects of these drugs come along free with the medication!!

But what is curtailed?.....the immune system's predicted attack on the inflammation around the myelin. And what continues to usually happen in all these cases....disease progression. If MS was an auto-immune disease (meaning the patient's immune system was the sole cause of the inflammation in the first place) don't you think that these drugs would have a far greater and long term positive effect? They don't and the MS research world continues to try different and more powerful immune system altering drugs in the hope that they are the answer. Well, so far they aren't and haven't been for the past 15 years and I see nothing to change my opinion on them.

I have to agree with Wesley on this....we simply don't know what is causing the MS in the first place and can't say one way or the other if the immune system is the original culprit.

Harry

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Hi Bob,

I'm at a loss in how to argue with you because I like to stick reasonably close to reality. In your response you talk of the immune system attacking the inflammation...now that's something I've never heard of. Is that actually a theory or a typo?

Gee, I didn't think we were arguing....I thought everyone here was expressing different opinions and ideas in a rather decent manner. If you consider that as "arguing", then I guess I can't do much about it other than indicate to you that I have no animosity whatsoever to your or anyone else's opinions.

I'm not sure why you don't understand the mechanism on the immune system going to the supposed defense of the myelin. Something, which nobody knows, is obviously causing inflammation at the myelin sites. The immune system normally sits around and keeps an eye out for something to go wrong in our system. When this happens, it sends out various kinds of cells to attack the problem. I'm thinking that you feel the immune system is "causing" the inflammation in the first place in this situation and my opinion is that something else is causing the problem and the immune system is simply reacting to it.

In order to gain a basic understanding of the mechanisms responsible for MS I think you should start with this page from the National Institute of Health Medline

No matter which way you read this, in is still all theory that has not ever been proven. If you read Dr. Behan's work, (he is considered an EXPERT in MS)he disagrees with this as do others in field. And their ideas are theory as well. The basic fact remains that nobody knows and nobody has been able to prove their theory.

And for the hundredth time, I will go back to the autopsy on that young lady who died from a massive MS attack where they found no indication of any immune system activity around the huge lesion that killed her. Why?......nobody knows!!

Harry

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Thankyou all so much for your very informative and in depth replies .

I would love to know where you all find this information, there are so many websites out there about ms research etc that taking one glance at them gives me a headache.
For a disease that appears to be not very well understood there are so many theories, research, seminars, forums, etc that i honestly overwhealm myself with information overload.

I don't know exactly what i meant by ms "strains'.

I just often wonder if ms is more than 1 disease, perhaps a group of similar diseases that stem from the one "strain"
I'm a registered nurse and i have seen both ends of the ms patient spectrum and i can't believe how the same disease can have one person paralyzed and another out running marathons with perhaps a tingling finger

So many questions that i know there are no answers to but it's very interesting to read all of your replies.

Elly

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Hi Bob,

I've been using that figure of speech all along (arguing) and you were never opposed to it before. I don't have any animosity either, never did. Frustration? YEAH!

Guess I must have missed it in the past messages....sorry! You feel frustrated with MS research after only recently becoming involved with it....you can imagine how I feel after following this for over 40 years!!

At any rate, maybe I've pushed this thing too far. I'm never going to convince you and you're never going to convince me. We should just end this autoimmune conversation and I'll just have to wait for all the fact to come in order to get you on my side.

This situation between the two of us is exactly what has been happening in MS research for decades and is perhaps why the results have been so abysmal for so long. Back in the late 40's and early 50's when Dr. Jonez was treating thousands of patients with IV histamine and seeing 80% of his patients get relief from their symptoms, his opponents (autoimmune camp) were ridiculing his work. Jonez died and so did his work. Now some universities are researching histamine's involvement with MS (over 50 years later) and discovering there may just be a big connection!

Don't worry, I'm not the kind of guys who enjoys saying "I told you so". Oh, you can bet that I am going to say it....repeatedly. But I won't enjoy it

I think perhaps that I will more likely be in a better position to say this?

I know that is going to cause me to hear from Harry Z but sometimes long and commonly held assumptions really are true

And quoting Betrand Russell.....The fact than an opinion bas been widely held is no evidence whatever that it is not utterly absurd; indeed in view of the silliness of the majority of mankind, a widespread belief is more likely to be foolish than sensible.

I rest my case

Harry

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I started looked through this thread thinking it was going to be about the theory that MS is more than on illness.

Strains? I don't know, it's an interesting thought.

Benign? I'd not want to have this diagnosis. From what we know about MS, it's very doubtful that it's benign. I'd not want to be sent home for 10 years feeling comforted that there was nothing really to deal with. I think this "benign" diagnosis might lull folks into a false sense of comfort.

Do we have this sort of diagnosis in the US? Never heard it before.

On my original thought, I do think there is a stong likelihood that MS is a symptom and not an illness. I think that it's likely that there are several illnesses, causes, viruses, mutations, etc. that might lead to the MS symptom. I say this because there is soooooooo much variability in the risk factors, theories and determinant probrabilities. Meaning, all the stuff about distance from the equator, identical twins and mononucleosis could very well be valid and true, but for different events that bring about the symptom of myelin reactive white blood cells.

Perhaps it's really all about a number of different ways cross presentation can occur. Just my thoughts, at least the ones I'm having right now. napay