viruses again

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viruses again

Postby dignan » Wed Mar 21, 2007 8:46 am

This is an abstract from 2004 that I hadn't seen before. It suggests the possibility that when present simultaneously, endogenous retrovirus and herpesvirus have a synergistic effect, and not in a good way. It is interesting as the multiple viral trigger possibility has been studied a bit.



Simultaneous presence of endogenous retrovirus and herpes virus antigens has profound effect on cell-mediated immune responses: implications for multiple sclerosis.

AIDS Res Hum Retroviruses. 2004 Apr;20(4):415-23.
Brudek T, Christensen T, Hansen HJ, Bobecka J, Moller-Larsen A.
Department of Medical Microbiology and Immunology, University of Aarhus, DK-8000 Aarhus C, Denmark. tb@microbiology.au.dk

Retroviruses have been suggested as possible pathogenic factors in multiple sclerosis (MS), supported by the observation that endogenous retroviruses are activated in MS patients. Different members of the herpes family of which several are neurotropic have also been suggested as factors in MS pathogenesis. Further, interactions between retroviruses and herpes viruses have been implied in the development of MS.

The objective of the study was investigation of cell-mediated immune responses of MS patients to retrovirus and herpes virus antigens, particularly antigen combinations, with analyses of the influence of retrovirus antigens on cellular immunological reactivity toward other viral antigens. Cellular immunity as measured by blast transformation assays was analyzed using freshly isolated peripheral blood mononuclear cells from 47 MS patients and 36 healthy volunteers.

Combinations of the endogenous retrovirus HERV-H and herpes virus antigens resulted in highly increased cellular immune responses among both the MS patients and healthy subjects. The increase was synergistic in character in most samples. Very pronounced effects were obtained using HHV-6A and HSV-1 antigens. Blast transformation assays combining antigens from two different herpes viruses or combinations of measles and herpes antigens showed no synergy.

The obtained data indicate a pronounced synergistic effect on the cellular immune response when retrovirus and herpes antigens are present together. The cause of the synergy is unknown so far. The effect on the immune response may influence the disease progression.

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HHV-6A

Postby gwa » Wed Mar 21, 2007 11:04 am

HHV6-A is proposed as a possible cause of MS on this MS group. They have a lot of info related to the herpes virus and MS.


http://p205.ezboard.com/multiple-sclero ... esclerosis
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Postby TwistedHelix » Wed Mar 21, 2007 11:07 am

That's an interesting new slant, Dignan...just when you thought MS couldn't get any more complicated....

Dom.
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Postby BioDocFL » Wed Mar 21, 2007 12:22 pm

Endogenous reverse transcriptase activity is what I have been harping on. If a reverse transcriptase becomes active in a cell, it can start reverse transcribing RNA to DNA. That DNA could be interpreted as foreign DNA since it would be hypomethylated like bacterial DNA. Proteins associated with the DNA and perhaps the RNA would then be interpreted as foreign, guilt by association. I've gone into this before and it is a lot more complicated than just the reverse transcriptase activity but this is the research path that should be studied for lupus and MS. It points to a non-immune cause of autoimmune diseases. And it points to the possibility of epigenetic changes being involved, (the opening up of previously sequestered genes) and not necessarily genetic mutational changes.

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Postby daisy » Fri Mar 30, 2007 3:34 pm

Wesley - your post on Endogenous reverse transcriptase activity is very interesting. You wrote "It points to a non-immune cause of autoimmune diseases. And it points to the possibility of epigenetic changes being involved, (the opening up of previously sequestered genes) and not necessarily genetic mutational changes. "

Since you have been researching this angle, do you have any theories on what are the most likely candidates for the epigenetic changes? Virus, toxins, genetically modified food proteins, other?

I have been really digging into the bench chemistry on substances that have epitopes that mimic MOG and MBP and so am very interested in your further thoughts on this subject.

Daisy
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Postby BioDocFL » Mon Apr 02, 2007 6:46 am

Daisy,

Thanks for your interest. I posted a lot of my theory about two years ago and since then have kept fairly quiet, mainly because I am so busy with my jobs. You can find the old discussions under the General Discussion topic called ‘Polyamines’, probably somewhere back around page 30 or 35 by now.

Now I have a lot more information that fits the theory. Instead of just writing another article limited to a few pages for some obscure journal to publish, one of my friends has convinced me to write a book explaining the ideas so I can do more depth. So I have an outline started listing topics for chapters I want to cover. For each topic, like ‘epigenetics’ or ‘X chromosome inactivation’, I would try to give enough basic explanation so laypeople could follow so that they can understand how I relate it to the theory. I would try to have a lot of figures too since I think that really helps get ideas across. The book would be towards lupus, MS, and others because I think there is a lot in common among these, just occurring in different tissues and therefore different molecular level consequences. I welcome any suggestions for chapter topics. Just hope I can find enough time to get the writing done.

So you are working on MOG and MBP? I am curious about what you might see if you compared the antibody binding of MBP in three conditions: MBP alone, MBP with spermidine, and MBP with spermine. Same thing for MOG perhaps. My thought is that an electrophoretic mobility shift assay (or some pull-down type assay) would show better binding of antibodies to the MBP+spermine complexes. The reason I am curious about it is some old articles:
Giorgi P. ‘Spermidine: a constituent of the myelin sheath?’ Neurosci Lett 1978; 10:335-340.
Russell D., Meier H. ‘Alterations in the accumulation patterns of polyamines in brains of myelin-deficient mice’ J Neurobiol 1975; 6:267-275.

If the first article is true, spermidine (+3) is part of the myelin assembly. The second article describes observations that two mouse strains that have spontaneous progressive neurodegeneration also have a shift in the spermidine/spermine ratio such that there is more spermine (+4) than in normal controls. My thought is that spermine (+4) may be substituting for spermidine (+3) or at least interfering in the myelin assembly. I vaguely remember seeing an article by a California group reporting slightly more positive charge in myelin from MS patients, but I haven’t been able to remember where I saw it.

My theory explains how spermine could increase abnormally in a cell with prior chromosome damage when the cell is stressed, which could be triggered by a virus, heavy metal, etc. This increase could also lead to chromatin disruption since spermine binds DNA quite well. This could then open up endogenous reverse transcriptases, such LINEs.
Also, polyamine (spermidine and spermine) synthesis requires S-adenosylmethionine, leaving less for DNA methylation, and further disrupting the epigenetic silencing that requires DNA methylation.

It’s a really complicated theory with a few loose threads still. I certainly welcome any questions or criticisms of it. And it is only theory, not proven fact...yet.

Wesley
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Postby TwistedHelix » Mon Apr 02, 2007 7:30 am

Hi Wesley,

I'm not even going to pretend to understand what you just said, but a few words just clicked into place in what remains of my mind:

The gene for cyclic nucleotide phosphodiesterase (CNP), is expressed in oligodendrocytes. If there is a problem with this, the cell will still produce myelin which appears to be absolutely normal, but inside the axon degenerates chronically and there is a build-up of amyloid precursor protein.
Spermine binds to Calmodulin, which is necessary for the activation of CNP and Calcineurin, and can therefore inhibit the production of both.

Does this have anything remotely to do with your theory, or am I just babbling inanely ?

Dom .
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Postby BioDocFL » Mon Apr 02, 2007 11:30 am

Dom,

Yes, spermine having a +4 charge means it can gum up a lot of things. It could out-compete calcium ions (+2) for the calcium channels and clog those channels up, for example. Or perhaps sodium channels. Or spermine could compete with histones in binding to DNA and potentially lead to opening up of previously suppressed genes. Polyamine (spermidine and spermine) synthesis is one of the most tightly controlled pathways normally with several redundant means of control, which suggests it is critical to control polyamines. I'll have to make a list of the possible interactions of spermine.

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Postby Lyon » Mon Apr 02, 2007 2:46 pm

Hi Wesley,

I've seen recent research which seem to provide evidence that faulty homeostatic expansion might instigate the process of autoimmunity.

I know this isn't exactly what you are talking about but might this somehow tie in with what you are talking about?

I guess exactly what I'm wondering...and since it isn't proven would have to involve guesswork, might the persistant presence of these opportunistic viruses create the need for homeostatic expansion often enough to raise the odds that sooner or later some aspect of the homeostatic expansion process might prove defective and start autoimmunity?

Bob
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Postby daisy » Fri Apr 20, 2007 9:55 pm

Wesley,

Thanks for your reply above. I went back and read through various posts on polyamines in the General Forum including yours. You are right - a wealth of information. Thanks for the kind nudge in the right direction. I find the posts to be informative and well done.

Regarding your idea for a book - excellent. Also, I agree with your idea to use the context of MS and Lupus together. Just curious - how will you explain basic cell biology - to a lay person if you will - and address epigentics - especially what external factors would you present as the most likely candidates as agents of change? How will you handle deimination, if at all? Also, don't know if this would be useful but since you are targeting the lay person - a review of the American Cancer Society research on the low percentage of genetic link to cancer and the high - 60% if my memory serves % link instead to life style might turn on some lightbulbs.

Can't really provide any additional thoughts to your posts on the MBP and MOB antibody binding conditions with spermidine and sperine and would like to spend more time studying your proposed explanations. My true interest is in non covalent electrical charges and in molecular mimeocry so your work is of tremendous interest. Thanks for taking the time to reply to my post. Daisy
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