This Is MS Multiple Sclerosis Community: Knowledge & Support

OddDuck,
You are probably right about the thymus still being around. It does start to shrink after birth. I think the point I was trying to make is that the mouse thymus is relatively more active later. I was trying to remember things I had heard about a long time ago, trying to think out loud on a tangent again. Still think the quaking and jimpy mice are interesting but I never did like working with mice. I'll try to stay more on a straight line in discussing the hypothesis.
As far as going to college, it could be enjoyable for you to take a few courses. I think you have a sharp mind and have taught yourself alot. A college course might give you a good framework in a topic to build your knowledge thoroughly. It's fun to listen to the lectures but stressful to take tests. Some courses can be boring, like statistics. I worked in computers in business software development for a number of years but was getting bored with it. Instead of jumping careers outright, I went to college at night for 1 1/2 years just to see how I would do while still working during the day. When I saw I could handle it, I quit work and went for a PhD. No guarantees I would make it through the first year though. I was pretty focused on why I did it though. I was interested in autoimmune diseases and was irritated that the antigen-driven possibilities weren't being researched much. With my background in systems analysis I think it helped me towards becoming sort of a theoretist type of biologist. What I do now is try to find new lead candidate compounds to inhibit polyamine enzymes using the computer for virtual screening. So I am working on the backend (as you say) while still hypothesizing about the frontend. Of course we are targeting cancer but I am seeing alot of parallels.
Would I do it all again? I don't know. It is a lot more interesting than business but it is too difficult to see a future in research since there are way too many people trying for the positions of any value. And, like in many fields, a higher position means more time away from pure research doing administrative stuff. Certainly was bored with business software development but was making alot more money. Actually before even starting the night school bit I took some aptitude testing that basically said I was bored with the business environment and that I should get into something more scientific and/or artistic.
I get bored easy and am used to constant change. Comes from being an Army brat.
Anyway, keep the questions coming and keep me honest if I'm not right on something.
Thanks, Wesley

That's funny, Wesley. Seems you and I are a lot alike.

I have a "background" in computers, business, blah blah blah, also. And as you can see, I jump all around with my thoughts, too. But even when/if I (we) go off the track for a bit, I usually come right back to the main subject at hand. LOL It's hard for some people to follow me, though, I think. You seem to do just fine.

And your reasons and motivations for doing certain things I can relate to, also. I get bored easily, too. Medicine, though, seems to have so MUCH going on (and like you mentioned the autoimmune diseases are very interesting, and I've had over a year of being in an MSer's shoes (whether they think I have MS or not - which as it stands currently, I have one neuro who says I do, another who says I don't - so I say I have definitely been determined to be one of the folks out there with the "predisposition" for MS), so I developed a passionate drive in the past year to try to be of some help. What or how, I have no idea, but the drive is still there.

Sam Hunter uses an analogy of what he calls the "threshold theory". It's like being right in the middle of a door frame. One step on either side of the door opening and you either show symptoms of MS or you don't. I'm constantly on the "threshold". The thing is, with the meds I'm on currently, it keeps my predisposition from developing into full-blown MS. (And yes, here's another plug for the meds I'm on - and Dr. Hunter is the only living eye-witness to the whole thing. We argued at first about their applicability for MS - it was ME who suggested we try it and use me as the guinae pig - and that's when he asked me to research it for him. So we can blame the whole thing on him....hehehe....) When it worked, well..........like he said "nobody will believe us". HAH! But where he threw up his hands in the air about it, I said "You watch me go!!" Hey, I don't have a reputation to lose by pushing the point or continuing to try to get someone to take a close look at it. As I said before.......many times..........I have substantive material coming out my ears!

Anyway, we'll see what becomes of both my research and of ME! LOL Hey, thanks for sharing your background with us! I always find it VERY interesting to know exactly who I'm dealing with, you know what I mean?

You can keep me engaged in this type of theoretical and analytical discussion for eons, I'm sure! I envy you having more "access" than I to actually get something done with it.

Anyway, I digress again. Carry on, Wesley! Back to polyamines. Don't stop now! Post when and as you can. You just never know who might be reading. I know Dr. Hunter and Dr. Moses both know who I am on here, and that I'm posting, and I've told them to follow it as they have time. What is my opinion? I know darn well Dr. Hunter pops in here now and again. And of course, I can't prove exactly what Dr. Moses meant when he said this, but when I visited him a couple of weeks ago, and gave him my research and told him to read it (yes, I told him to...LOL), Dr. Moses said YOU are OddDuck? And started to chuckle. So, we might be surprised who all DOES pop in here now and again. hehehe...............

Oh, and by the way, I just got back from having an EMG done at Vanderbilt. I'm so baaaaaad! LOL There were three male resident doctors in the room, and one female resident, ALL doing my EMG and asking me questions. Let's just say that during our discussions, I left them with a couple things to "think about", also.

They were trying to ascertain where to stick the needles, and I said "let's just do the left thigh and leg, and the right arm" and told them why. An older supervising doctor who was there started to laugh, and said GREAT! You just made it easy for us!

Deb

Ok, Wesley..........here's some homework.

X chromosome - B cells - antibody - lysis of oligodendrocytes, not apoptosis

T cells - DNA fragmentation - caspase mediated cell death - apoptosis of oligodendrocytes

So, which type of cell death are the oligodendrocytes undergoing (in MS) in your hypothesis?

Deb

EDIT: Wesley, I also posted another couple of new threads that I think you might consider perusing, as they may pertain to your research directly. One on IL4, and another regarding female predominance.

I hadn't thought about it too much. With regards to a polyamine related mechanism, I am picturing two types of cells under duress, those cells with an underexpression of polyamines (probably due to being short-changed when the cells split during mitosis and losing the active copy of important genes) and those cells that have overexpression of polyamine genes (perhaps gaining extra chromatin during mitosis or reactivating part of their inactive X chromosome). I know there are different paths of apoptosis but the first type of cell I think would go into a calcium/caspase apoptosis if the polyamines can't control calcium flow. But, I think there is a higher concentration of calcium in the mitochondria relative to the rest of the cytoplasm and nucleus, I might be wrong. But, if that is the case, damage to the mitochondrial membrane could release that calcium, perhaps from an overexpression of spermidine/spermine N1-acetyltransferase (SSAT) and polyamine oxidase (PAO). I believe that SSAT and PAO can create peroxides that can damage membranes but I am not familiar with that route. Anyway, calcium could come from two different directions, outside the cell and/or from the mitochondria. In the second type of distressed cell, if an increase in spermine in the cell starts disrupting chromatin in a cell that is still living, I believe some previously sequestered genes and pseudogenes could become active. I can envision ways in which autoantigens could be created from that, but it is not as simple as people might think, ie. not: previously sequestered gene is transcribed to a messenger RNA that is translated into a protein, a protein which the immune system attacks as a foreign protein. I don't think it's that straight forward.
Okay, now you've got me started. I should probably tackle how I believe there could be chromatin disruption that leads to further problems. This is probably the most complicated, wackiest part of the hypothesis. It is based a lot on lupus autoantigens but I think you will occasionally see carry over to MS and RA, especially when I get into reverse transcriptases.
I think I need to explain a little about the basic chromatin structure. Some of you may know this but please bear with me. I am trying to get some old pictures I made posted so I can refer to them. That would help. In the meantime...
DNA is normally double stranded and in the B-DNA form, which is a right-handed spiral (stick your right hand thumb parallel to the DNA chain and your fingers curl in the same direction as the strands curl around each other). The strands each have a backbone along the outside of the DNA chain made of alternating phosphate groups (phosphorus and oxygen) and ribose sugars (flat pentagon shaped carbon and oxygen structures). On the inside of the strands are the bases: guanosine (G), cytosine (C), adenosine (A), and thymidine (T). These are flat carbon, oxygen, nitrogen structures attached one base to one ribose. The two bases across from each other on the two strands are always paired as: G with C, or A with T. The pairs of bases are not fully connected to each other but are held by hydrogen bonds. They are attracted to the same hydrogen ion (a proton) but they do not share their electrons so it is weaker than the covalent bonds where electrons are shared. There are three hydrogen bonds between each G-C and two between each A-T, so that we can speak of stretches of DNA that are G-C rich as having greater attraction in the strands and so the strands can not be separated as easily. Due to the flat character of the bases, the base pairs can stack on top of each other. This stacking, the hydrogen bonding, and the phosphate backbones help maintain the integrity of the DNA chain. If a base is damaged, it can be replaced by matching the base in the opposite strand: G-C or A-T pairing. Strand separation is needed during transcription, repair, and replication when the DNA sequence (ex. GCATTTCCA....) is being read. During this though the phosphate backbones should maintain their integrity.
The two strands wrap around each other once every 10.5 base pairs on average. If they are overwound (ex. a turn in only 9.5 base pairs) that is said to be positive supercoiling stress. If they are underwound (ex. a turn in 12 base pairs) that is called negative supercoiling stress. The stress can be converted from overwinding or underwinding of the DNA spiral into what is actually supercoils, where the whole DNA chain warps into a loop. This is like twisting a stiff rope between your hands until it starts to bend with the stored up strain. You can see this conversion of supercoil stress if you take a rope and tape the ends together forming a circle. Then disconnect the rope ends and give it a bunch of twists and retape the ends. You will see the rope can remain strained as a circle or it can relax the strain by flipping into a figure 8 pattern. When this happens in DNA, it can reduce the linear storage requirements by 7x. This is part of how one meter of DNA can be stored in something as small as a cell. There is a lot of self-repulsion of the DNA in bending, however, because of the many negative charges along the phosphate backbones of the DNA. Histones are positively charged proteins that can form nucleosomes with DNA. Eight histones form a protein core and the DNA wraps 1 1/2 to 1 3/4 turns around this core in a left handed (negative supercoil) over the surface of the proteins. The histones neutralize about half of the DNA negative charges so the DNA is locally flexible enough to wrap around the proteins. About 145 base pairs are attached to the histones and another 55 (on average in humans) are in the linker region between nucleosomes. These nucleosomes appear as beads on a string when viewed under an electron microscope. The attachment of the DNA to the histones is not covalent, but is along the lines of hydrogen bonding between the negative phosphate groups of the DNA with the positively charged arginine and lysine residues (amino acids in a peptide/protein chain) in the histones. So these are not permanent connections. The histones' hold to DNA can be weaker if some of the lysine or arginine residues are methylated, which neutralizes the positive charge at that site, or acetylated, which converts the positive to a negative. So, if polyamines stimulate acetylation of histones, that could reduce the hold of histones to the DNA and open up the underlying gene. Also, the positively charged polyamines can bind to the DNA, competing with the histones or in other sites actually helping to hold the histone/DNA packaging. The nucleosomes can stack together, especially when histone H1 binds to the linker DNA further neutralizing the DNA's negative charges. When the nucleosomes are stacked, one could imagine polyamines binding to the DNA in two different but proximal nucleosomes acting as an additional piece of tape to hold that stacked structure. On the other hand, polyamines can stabilize Z-DNA, which is more rigid, less flexible than B-DNA. Z-DNA is a left handed coiling of the strands with 12 base pairs per turn. It can not bend over the surface of a histone so histones and Z-DNA are mutually exclusive. Z-DNA and nucleosomes both are forms of stored negative supercoiling so they compete for any negative supercoiling stress fluxing through the DNA locally. It takes about 5 Kcal/mol (ignore this, just an energy term) to initiate the flip from B-DNA to Z-DNA but then it only takes about 0.3 Kcal/mol for each additional base pair to flip. So once Z-DNA begins to form, it can grow and recede through a stretch of DNA, depending on the particular sequence (best is G-C rich, especially alternating methylated G-C base pairs, ex. GC,CG,GC). The moving section of DNA between Z-DNA and B-DNA is referred to as a B-Z junction and it can range from 3-12 base pairs. This is where there is unstacking and restacking of bases and is a site of disruption and vulnerability. I believe, but nobody has shown it, that this can be a site where enzymes might be able to access the bases more easily for such things as methylation or demethylation. Just one of my minor hypotheses. Anyway, polyamines (especially spermine) can stabilize Z-DNA and perhaps help encroach on a nucleosome's hold.
One of the areas of debate in research is what happens to the histones when a polymerase is reading through the gene. Somehow the DNA strands have to be unwound and separated, and at least several bases of one strand have to be released from the histone connections. This is where it starts to get complicated (ha). The polymerase is separating the strands (negative stress) as it reads the gene but in doing so it generates an equal amount of positive stress ahead of it in the DNA. This positive stress can be prevented from building up too strong by its encounter and neutralization by the negative stress stored in a nucleosome. This linearizes the DNA in the nucleosome, which weakens the overall nucleosome structure. Do the histones come off as one group, do they come off individually or two at a time, or does the polymerase somehow negotiate its way through the nucleosome one or two histones at a time without them coming completely off of the DNA? That is the problem being researched still. The nucleosome can reform behind the polymerase, however, because of the negative stress that is still available after the strand separation. This movement through a nucleosome is rapid, so the histone/DNA interactions are only temporarily disrupted. However, Alexander Rich at MIT has shown that, if polymerases are going through a gene very frequently, Z-DNA may actually form behind the polymerase. This can slow the following polymerases so that there is a modulating effect attenuating the pace of transcription for that gene. We are also finding that there are some proteins that bind Z-DNA, perhaps giving it longevity. So between these proteins, polyamines, histones, and a lot of other factors, there is a dynamic character to the stresses and accessibility of DNA at different sequences. The human genome project of sequencing the DNA was child's play compared to what it will take to determine an epigenetic map and a transcriptional activity map of the genome. This is too dynamic probably due to histone, DNA modifications, the local ionic milieu (calcium, magnesium, polyamines), the local supercoiling stresses, and other factors bound in the chromatin. Each protein that binds DNA can impart some negative or positive stress into the DNA and the local stress situation can have a lot to do with how tightly a protein holds on, and it can affect the integrity and continuity of protein complexes assembled on DNA. There are enzymes called topoisomerases that are continually active cutting a strand or both strands, twisting the DNA, and then religating the strands in order to adjust the supercoiling stress. Overall the genome is held in a slightly negative supercoiled state since each nucleosome holds a net of one negative supercoil and nucleosomes occur on average every 200 base pairs. Nucleosomes have some preferences as to the sequences that they will bind but it is not real specific. So we sometimes speak of nucleosomes as positioned, especially near the beginning of genes. With the modifications to histones (acetylation) and the competition for stress storage, sometimes a nucleosome can slide a little, instead of completely being removed. Even if it is a displacement of just half the 145 base pairs, sliding 70 base pairs may be enough to open up the initiation site of a previously sequestered gene or pseudogene. So think about how an increase in available free spermine and stimulation of histone acetylation could affect this. This will be important in the biggest, wackiest part of the hypothesis that leads to autoantigen generation.
Let's revisit the genetic versus epigenetic definitions. A example of a genetic change would be changing the DNA sequence at one site from a G-C base pair to an A-T base pair, or vice versa. There could also be insertions or deletions of base pairs at a particular site. These change the DNA sequence and permanently change the code so that it will mean (in many cases) a permanent change in the resulting protein. An epigenetic change could be acetylation of histones at a site that loosens the nucleosome's hold and allows transcription of the underlying gene. If the histones are deacetylated and the nucleosome grabs back on tightly, the gene can be shut off. It could be turned on again later. So no permanent change has occurred to the DNA sequence and the protein is still the same when translated.
If you can get to some pictures in a molecular biology, biochemistry, or general biology textbook, you might see some of this better. I will keep trying to post some of my old seminar pictures that are geared towards this type of discussion.
So histones help package DNA to reduce its storage requirements and its accessibility. When nucleosomes form, it is like beads on a string and those can be stacked together so that it looks like clumps of beads, further reducing the storage area required and further reducing the accessibility. This is how heterochromatin like much of the inactive X chromosome may appear. I haven't mentioned about the heteronuclear RNA that appears to play a role in chromatin structure and dynamics. That's because not a lot is known about how the RNA figures in. XIST RNA is an example, but it may be somewhat unique. It helps in X inactivation but exactly how is unclear. One thing may be that it helps recruit methyltransferase enzymes that methylate DNA and histones. Also, macroH2A has RNA binding sites in its structure. Perhaps macroH2A provides anchor points for XIST RNA and other controlling RNAs along inactive chromatin. RNA may wind up being an important part of chromatin in an epigenetic sense. And with that, polyamine/RNA interactions may be an important epigenetic control mechanism but there is little knowledge so far on polyamine/RNA/chromatin relations.
I'll explain in the next post how I think strand breaks could be involved in the chromatin problems I believe are occurring in autoimmune diseases.
Later.
Wesley

Ok, Wesley. But remember, the connection that needs to be made is not just how all this relates to autoimmune disease, but how it relates to multiple sclerosis.

Forgive me, but how much research have you done into MS itself? It's a whole different puppy, you know.

I look forward to your next post.

Deb

OddDuck,
I am trying to lay the groundwork to explain how unrepaired DNA damage and fragmentation of chromatin could occur. And I think polyamines play a part. I am trying to explain the hypothesis in terms of MS. That was why I brought up things like the quaking and jimpy mice, the effect of polyamines on the blood-brain barrier and ion channels, and the chromosomal abnormalities observed in MS. I am now getting to how sequestered genes could be expressed, which could include reverse transcriptase activity and expression of synctin, a protein recently mentioned in MS as originating from retroviral activity and the reverse transcriptase, HERV-W, which has been mentioned in MS. If this is all old hat for everyone then perhaps I have not done enough research. If it is new to many people, then perhaps I have done a lot of research with a new perspective. If fragmentation of chromatin and loss of epigenetic control don't sound like valid possibilities for a hypothesis on MS, let me know why. I still believe that MS, lupus, and RA have similarities which can help us to understand them and that is why I speak of all of them but try to point out how things might be different in each. I doubt that I can explain why each symptom occurs in each disease though.
Hope that clears things up. Wesley

No, what I am saying is there are some KNOWN things about MS. MHC is one of them. I am not asking anything that has anything to do with "symptoms", and I know you realize that, correct?

It's when I ask certain questions of you that you aren't able to answer is what makes me wonder is all.

So, at the end of the day, what does your theory say is happening to the oligodendrocytes.............are they degenerating due to lysis (and/or necrosis) or apoptosis?

How do polyamines interact with MHC? Those are pretty simple questions, actually. I'm not trying to be difficult, but you had said you "hadn't thought about it too much". But.............that HAS to be thought of, or no theory will relate to MS at all.

Please don't get upset or mad. I warned you up front that we (I) might pose some probing questions.



I'm still listening to you. How far, though, did you get with the MS researchers you did contact? What was their actual feedback to you? I'm truly curious and interested in what they said.

Deb

OddDuck,
As I've said, I was originally interested in lupus and thought there were parallels in other diseases. I am now in cancer research but am still interested in developing the hypothesis. I have not worked on experiments directly related to MS, if that is what you are asking. I am in no way an expert on MS, do not claim to be, do not expect to be. But, as I have said, I have some ideas that I believe may relate to it and have not heard them discussed. I have worked on experiments related to autoimmune diseases in general, relating to X inactivation. And I have worked on experiments related to antigen presentation and secondary signals that trigger activation of T cells. Within that, MHC was involved. However, I am not an expert on that area and have not dealt with it in a long time. Sure a hypothesis must be able to explain the MHC component or at least not contradict what is known but, if one is thinking of the autoimmune aspect as secondary to neurodegeneration (as I am), then explaining the details of antigen presentation and MHC in relation to the hypothesis is something that would be secondary to developing ideas on the neurodegeneration. There are many things a hypothesis must explain including female predominance, any photosensitivity, why is myelin targeted, how would any reverse transcriptases be involved, why can so many different things trigger bouts, etc. As I have said, I have not filled in all the holes in the hypothesis but am trying to find where the holes are. In some areas (in most areas) there is more learning and thinking to be done on my part to relate the hypothesis to a particular fact. My feeling is that polyamines may be bound to peptides and/or nucleic acid fragments that are being presented, altering the epitopes. This is then interpreted as foreign material by the T cells, APCs, and antibodies. I haven't seen much research on how polyamines could be interfering with antigen presentation and I have not done any experiments on it. ' How do polyamines interact with MHC?' I don't know and I don't think anyone has looked at that in detail. There are antibodies that are now commercially available that can target polyamines, so there appears to be greater possibilities of doing experiments studying epitopes with regards to polyamine interactions now. The secondary signalling in antigen presentation could be tested +/- polyamines to see if there are differences. I had thought about those things but was not in a position to test them and had other areas to develop.

As far as oligodendrocytes, in a previous post I described two possible types of distressed cells based on chromatin distribution and over and underexpression of important genes. The ones that were underexpressing I felt would go into apoptosis fairly soon. The cells overexpressing the genes perhaps go into apoptosis later or necrosis, I can't say which but they might be living long enough to generate some of the autoantigens through a mechanism I have yet to describe. So I am presenting the idea that there are two or more types of distressed oligodendrocytes that may be in close proximity. Can I prove it? No. Just hypothesis on my part. I haven't seen where anyone has discussed different types of distress in oligodendrocytes. Seems like a valid question to explore.

As for how far I have gotten with MS researchers... I have presented in seminars an earlier version of the hypothesis on the autoantigen generation to rheumatologists, immunologists, and molecular biologists. But, in each group I felt that the rheumatologists didn't understand the X inactivation and chromatin dynamics well enough and the molecular biologists didn't know enough about the diseases. It's difficult to explain it all in a seminar. I have sent my ideas to lupus big names but, if they responded it was like a short cold, 'interesting hypothesis, good luck testing it.' response. Again, were there areas they didn't understand, were they way ahead of me on the same hypothesis, were they holding their cards close or did they just not have any cards? I don't know when I am confronting the dogma about the diseases being immune system-driven because they don't always come out and say it. One thing that I feel happens is that sometimes a person will hear one thing that they don't agree with and don't want to consider the hypothesis any further or try to see how their difference in opinion could be resolved. As far as peddling the hypothesis to experts: Who is an expert in relation to a disease if their knowledge doesn't include the basic facts of how the disease occurs and how do you cure it? Those are big gaps in their expertise. I have published earlier versions of the hypothesis before and have gotten hundreds of requests for reprints, which I send out. I don't know the motives or capabilities of the requestors but I am glad that many of them seem to be early in their careers so perhaps some new open minds will be interested in the hypothesis. I am willing to share my ideas, which doesn't appear to be the norm in research. If you want to pass the ideas along to someone in particular in relation to MS research, please do.
Wesley

As a matter of fact, I have been passing them on, Wesley. It's better coming from you personally, though, but I believe you know that.

And thanks..........you've cleared up a lot of questions I had.

Yes, I hate to say it, but that was sort of my response to you, also, wasn't it? "Good luck testing it". Although, I don't believe I meant it in the same context.......i.e. as a dismissal at all. I meant it as I think I understand that that's the response you'll most likely get.

I totally understand your frustration in getting someone to listen and consider your thoughts about all this. I truly do.

And the problem you will probably have with immunologists is that they will be focused, as I mentioned before, on what you would suggest as possible treatment. The key word is "integrative" when you refer to MS. Even though MS research ITSELF is fragmented.

Now here's where I think you might have identified the pulse of the issue. Polyamines and MHC. My gut is telling me that there is where you might have better luck grabbing ALL of their attention. From what I can tell, the one thing they all have in common (geneticists, immunologists, molecular biologists) is the MHC factor in MS.

Remember, Sam Hunter himself does at least understand your frustration in research with the "can't prove it" part. So, there are some immunologists who at least can "relate" to that. But on the other hand, they know it HAS to be proven somehow or at least "backed" somehow (either by pure reputation from someone in the field, or by money, even though I hate to say that).

Oxymoron, huh? Welcome to the world of MS.

Carry on, though, Wesley! For what's it worth, I AM interested.

Deb

EDIT: By the way, referring to whether they were way ahead of you in some areas, etc., I found myself while investigating some of your posts where you might indeed find that, also. Some researchers HAVE gone somewhat beyond some of the areas you have touched on, but again.............that attitude will depend on who your audience is. Remember to research your audience. I was torn apart initially by someone on this board over the presentation of my initial paper (which was very valid). I probably SHOULD have re-written it for purposes of posting on this Board, BUT......in my defense, it was originally written for presentation to Sam Hunter, who was my sole audience and who had requested it in the first place. Therefore, I only presented the "highlights" and wrote it in such a way so that I could be assured he would read it, and in such a way as to not insult his intelligence (or at least I tried). But he also knew me well enough to know that I was a researcher, also, and when I offered to give him my substantive material, he said there was no need. (He knew I'd bring in a truckload! LOL)

Okay, so poylamines and MHC is an area I need to work on to get more detailed in the hypothesis. I may actually have the possibility of doing experiments on that in the future, but it would only be on the side. I think there could be an angle with regards to the autoimmunity that sometimes arises in cancers. We have some people looking at that where I work so perhaps I can talk with them. In fact, if I can find any crystal structures at the Protein Data Bank on the web of MHC complexed with material, perhaps I can do some virtual docking of polyamines to the complex and see how they might interact. That is different than what we usually do but maybe I could get a paper out of it. I've got more than enough other work as is though, which I need to get back to now.
And as far as possible treatments (and prevention), that's why I am where I am now. If we find good inhibitors for cancer treatment, we are already set up to take them at least as far as testing in mice. Then it would get into clinical trials and all. The same compounds could be looked at for other diseases that might involve polyamines.
I'll try to continue posting more details of the hypothesis in the next several days when I can.
Wesley

Wesley,

This might be an interesting article if you can find it. I didn't have access to it online. Maybe you can get ahold of it.

Deb

Clinical and Experimental Immunology
Vol. 138 Issue 1 Page 164 October 2004
Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus
M. MANDEL, M. GUREVICH, R. PAUZNER, N. KAMINSKI, A. ACHIRON

OddDuck,
I couldn't get the full article but the abstract was interesting. They looked at peripheral blood mononuclear cells in MS, SLE, and controls and found a signature pattern of 1031 genes for MS, 1146 genes for SLE, and the MS and SLE had a common gene expression signature of 541 genes. So, as I understand it, the MS patients differed from controls in 1031 genes but were similar to SLE in 541 genes. The common MS & SLE pattern corresponded to genes coding for proteins involved in apoptosis, cell cycling, inflammation, and regulation of metalloproteinase pathways. The MS had some additional characteristics of up expression of of adhesion molecules and down expression of heat-shock proteins. SLE had additional characteristics of DNA damage/repair.
It would be intereting if, instead of cells in the blood, they could compare cells from lesions in MS, and also skin fibroblasts and kidney cells in SLE.

Wesley

Now you are getting into Dr. Claudia Lucchinetti's realm of expertise.

It does sound interesting.

Deb

Wesley,

So how does the down expression of heat shock proteins in MS that they found affect your hypothesis, or does it at all? You know, I ran across some other information about heat-shock in MS, but at the time I was focusing on another physiological aspect, so I only put it in the back of my mind.

(*sigh*.......I guess it's time to go bone up on heat shock proteins. )

Deb

EDIT: Naw....actually, it's time to go eat dinner!

As I said, it would be better if they could have used cells from MS lesions. See the article below where there was an increase of heat shock proteins in MS lesions. As I understand it, heat shock expression typically goes opposite to the expression of the cell's other genes. The peripheral blood cells may not be under a heat shock stress but are responding to other stimuli. The cells in a lesion are under stress and are probably doing a lot of heat shock expression. What could be disrupting them? hmmm, I wonder. Of course I could always make a suggestion.
Art over at the Boston Cure Project wants to start tackling reverse transcriptases with regards to MS. That should be interesting. I have a lot more of my hypothesis to explain, part of which is how the endogenous reverse transcriptases could become active. Still doing the ovarian cancer grant writing routine though.
Later, Wesley (hsp abstract below)
International Immunology, Vol. 15, No. 2, pp. 241-249, February 2003
Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains
Hanna Cwiklinska1, Marcin P. Mycko1, Otgonbajar Luvsannorov1, Bogdan Walkowiak2, Celia F. Brosnan3, Cedric S. Raine3 and Krzysztof W. Selmaj1
Heat shock proteins (hsp) are known to facilitate the generation of specific immune responses by chaperoning proteins and peptides involved in T cell activation. Hsp have been shown to be strikingly elevated in multiple sclerosis (MS) lesions. The unique chaperonin properties of hsp70 have allowed identification of immunogenic proteins bound to it by the ex vivo demonstration of hsp associations with proteins implicated in the immune response. We have investigated the association of hsp70 with myelin basic protein (MBP), myelin proteolipid protein (PLP) and myelin oligodendrocyte protein (MOG) in MS and control brain tissue. In co-immunoprecipitation experiments, in all samples of MS brains examined (n = 3), but not control brain tissue (n = 3), direct association of MBP with hsp70, but not with hsp90, was found. In some MS brain samples, association between PLP and hsp70 was also seen. In similar co-immunoprecipitation experiments on brain tissue obtained from mice with experimental autoimmune encephalomyelitis (n = 5) induced by immunization with PLP peptide, specific association of hsp70 with PLP and MBP was found. Using surface plasmon resonance we demonstrated specific binding of hsp70 with MBP in vitro. Analysis of the amounts of MBP bound to hsp70 yielded a molecular ratio of MBP binding to hsp70 at 6.5:1. MBP complexed with hsp70 was taken up at significantly higher rates by antigen-presenting cells than MBP alone and enhanced MBP-specific immune responses. These results indicate that hsp70 specifically associates with MBP in MS brain tissue. This association might be relevant to the enhanced immune recognition of MBP in MS.