MS linked to Mono

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

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Postby gwa » Sun Jan 14, 2007 3:42 pm

Ian,

I only get a blank white screen when the link you posted is clicked. Is it just me or are you up to tricks with the imagination now?

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Postby Lyon » Sun Jan 14, 2007 4:40 pm

Hi gwa,
The link may be working for you now but I copied and pasted...just in case.
Bob
The role of Epstein-Barr virus (EBV) in triggering disease activity in MS

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.
Bob
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Postby Lyon » Sun Jan 14, 2007 7:09 pm

Thanks for yet another interesting link Ian.
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.
This is yet another of the multitude of seemingly nonsensical situations surrounding MS. How could so many "infectious agents" considered separately be associated with MS onset/relapse? It just isn't logical.

It would be much more likely and believable if there were a common denominator linking them together. If there is any truth to that study I linked to earlier regarding faulty homeostatic expansion (I just went back to borrow that link to repost here and realized that I never posted it) then it makes complete sense of this otherwise nonsensical situation.

Basically the idea is that these researchers http://tinyurl.com/sc4h7 found evidence that a faulty homeostatic expansion process can initiate the autoimmune process. If true, that also seems to mean that anything which creates a situation requiring a call from the body for homeostatic expansion could be said to lead to the initiation of the autoimmune process.

I think it's valid that in Ian's article, when describing these "infectious agents" the researchers not only used the commonly used "dormant" but also "latent" and I'm sure that's intentional. "Dormant" brings to mind comfortably sleeping but in reality these infectious agents have been chosen through the evolutionary process for their opportunistic tendencies.

Even though after the initial infection our immune system has their number, these infectious agents aren't comfortably resting, they are waiting for a moment of weakness and occasionally lunge like a cornered dog. It wouldn't take a huge stretch of the imagination to consider that their occasional lunges do play some part in the relapsing remitting cycle.

At any rate, I think grouping these "infectious agents" together as things which instigate homeostatic expansion is a lot more believable than considering them separately to each have some kind of unique relationship to MS incidence.

Bob
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Postby BioDocFL » Mon Jan 15, 2007 9:54 am

I think these agents (viruses and also throw in heavy metals) could be related in that they can induce stress-related gene expression in a cell. If the cell has suffered chromosome damage from low levels of vitamin D and the resulting genomic instability that can entail, then the cell's stress response could be exaggerated and lead to an over-reaction, over-expression of some genes that have lost their normal control.
Mutation Research 475 (2001) 69–88
Review
Vitamin D and genomic stability
Malay Chatterjee
Abstract
1a,25-dihydroxyvitaminD3 [1,25(OH)2D3] has been shown to act on novel target tissues not related to calcium homeostasis.
There have been reports characterizing 1,25(OH)2D3 receptors and activities in diverse tissues such as brain, pancreas, pituitary,
skin, muscle, placenta, immune cells and parathyroid. The receptor hormone complex becomes localized in the nucleus, and
undergoes phosphorylation by reacting with a kinase. This form of the receptor then interacts with the Vitamin D responsive
element of target gene and modifies the transcription of those genes to develop the action. The modulation of gene transcription
results in either the induction or repression of specific messenger RNAs (m-RNAs), ultimately resulting in changes in protein
expression needed to produce biological responses. Genes for carbonic anhydrase that are expressed at high levels in osteoclast
are known to be involved in bone resorption and Id genes role in osteoblast–osteoclast differentiation reflects the genomic effect
of Vitamin D on bones. Genomic action of Vitamin D also explains the biosynthesis of oncogenes, polyamines, lymphokines
and calcium binding proteins. However, there is a possibility that some of the actions of 1,25(OH)2D3 may be mediated by
non-genomic mechanisms and may not require the binding to Vitamin D receptor (VDR).
Vitamin D offers a protection from genotoxic effects of Vitamin D deficiency by increasing the insulin receptor gene expression
and BSP (bone sialoprotein), bone-remodeling by decreasing the osteopontin (OPN) m-RNAs, maintaining the normal
epidermal structure and enamel matrix. Gonadal insufficiency in Vitamin D deficiency was corrected by vitamin mediated
direct regulation of the expression of aramotase gene. The supportive role of Vitamin D in placental function is also evident
by its influence on human placental lactogen (hpl) gene transcription accompanied by increase hpl m-RNA levels. Further
role of Vitamin D is envisaged in identifying cyclin C as an important target for Vitamin D in cell-cycle regulation.
Vitamin D at physiological concentration has been found to protect cell proteins and membranes against oxidative stress by
inhibiting the peroxidative attack on membrane lipids. Vitamin D, at a concentration range of 210−8–510−8 M, induces
apoptosis in most cancer cells, stabilizes chromosomal structure and prevents DNA double-strand breaks induced either
by endogenous or exogenous factors. Vitamin D is also effective in stimulating DNA synthesis in adult alveolar II cells and
provides a novelmechanism of modulation of epithelial cell proliferation in the context of lung development and repair against
injury. The regulation of various proto-oncogenes (c-myc, c-fos, c-jun), differentiation inducing properties, antiproliferative
effects on keratinocytes and inhibitory effects in several human malignancy ranks Vitamin D as a novel hormone that may
have physiological and clinical implication in the carcinogenic process.


Notice the expression with regards to vitamin D "stabilizes chromosomal structure and prevents DNA double-strand breaks induced either by endogenous or exogenous factors."

So someone who has low vitamin D could have an accumulation of DNA double-strand breaks and other damage that can lead to chromosomal fragmentation, improper distribution of chromatin to daughter cells, and opening up of previously sequestered genes. One gene I have pointed to previously is spermine synthase on the X chromosome. With two X chromosomes, normally one is inactive the other active. But with chromosome instability, leading to fragmentation and/or low methylation, perhaps both become active leading to over expression of spermine synthase from both copies of the gene instead of just one. Look at the following:


'Methylthioadenosine, a potent inhibitor of spermine synthase from bovine brain' Pajula RL and Raina A, FEBS Letters (1979) 99:343-345.

'Methylthioadenosine reverses brain autoimmune disease' Moreno et al. Ann Neurol 2006;60:323-334.

Granted, these authors used EAE rats and attribute the reversal to suppression of the immune system's autoimmune attack but at least someone is finally talking about the right enzyme as far as I'm concerned. If spermine synthase is over-active it can reduce S-adenosylmethionine needed for methylation and reduce the spermidine needed for myelin formation and hypusine formation that is essential for translation. It can also alter the inactions of vitamin D receptor with its targets. An excess of spermine can stabilize Z-DNA, which is a major auto-antigen in lupus.
The genomic instability could also lead to expression of LINEs and SINEs which then give the appearance of reverse transcriptase activity and would put a big strain on the cell's S-adenosylmethionine needed for methylation. See:
'The long (LINEs) and the short (SINEs) of it: Altered methylation as a precursor to toxicity' Carnell AN and Goodman JI Toxicological Sciences (2003) 75:229-235.


Does disruption of the X chromosome as I am proposing have a relation to autoimmune diseases? See:

ARTHRITIS & RHEUMATISM
Vol. 54, No. 4, April 2006, pp 1270–1278
Identification and Characterization of an Xp22.33;Yp11.2
Translocation Causing a Triplication of Several Genes of the
Pseudoautosomal Region 1 in an XX Male Patient
With Severe Systemic Lupus Erythematosus
Pierre Chagnon,et al.
The X;Y translocation break point sequence in
an XX male patient with prepubertal systemic lupus
erythematosus (SLE) was characterized with the intention
of identifying a predisposing gene(s) for SLE.
Spectral karyotyping of the patient’s metaphase chromosomes
showed normal autosomes and 2 X chromosomes,
one of which displayed a small portion of the Y
chromosome. Using a Y chromosome polymerase chain
reaction (PCR) walking strategy and inverse PCR, we
found that the abnormal recombination occurred between
retroviral long terminal repeats located at
Xp22.33 (position 0.95 Mb; inside the pseudoautosomal
regions) and Yp11.2 (4.20 Mb) downstream of the
sex-determining region Y (SRY) gene. The complete
DNA sequence of the break point was determined,
revealing a partial duplication of the pseudoautosomal
region 1 (PAR1) in the derivative X chromosome and
causing a partial trisomy of the 12 known genes located
between the interleukin-3 receptor  (IL3RA; position
1.1 Mb on the X and Y chromosomes) and CD99
(position 2.2 Mb) genes inclusively. All other X chromosome
genes were present as 2 copies. Real-time quantitative
PCR confirmed the presence of 3 copies of each of
the 12 genes in the patient’s genomic DNA. We also
found that RNA for 1 of the candidate genes was indeed
overexpressed in the patient’s blood as compared with
normal subjects. Taken together, the uniqueness of the
translocation, the rarity of severe prepubertal SLE in
males, and the presence of SLE in some patients with
Klinefelter’s syndrome (who have a triplication of the 2
PAR regions) point to a possible relationship between
the partial triplication of the PAR1 region and the
development of SLE.

This disruption of the X by insertion of a small fragment of the Y in an XX male is enough to give the person a male phenotype but also appears to give the person a susceptibility for lupus. This insertion location is near the spermine synthase gene at Xp22.1. Although the insertion is distal to Xp22.1, my belief is that it disrupts the overall X inactivation (chromatin structure) process in that region, including proximally into Xp22.1. There are other case of X-linked chronic granulomatous disease with disruptions at Xp21.2 leading to lupus. The authors of the Arthritis & Rheumatism article above cite two genes that are particularly interesting: the IL3RA gene for a subunit of the interleukin-3 receptor and CD99, a cell surface molecule involved in adhesion and T cell apoptosis. These two genes would be more easily seen as culprits than the spermine synthase I'll admit but they all could be problems when the chromatin is disrupted.

It's been two years since I wrote about polyamines in detail. I probably should try to write out my theory again with the newer material I am finding and get it published somewhere. It just doesn't seem to interest the autoimmune research world. I get more interest from the cancer researchers though in relating genome instability, polyamines, and tumor growth.

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Postby becca » Mon Jan 15, 2007 9:58 am

WTF.. :?
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Postby BioDocFL » Mon Jan 15, 2007 10:20 am

You are correct in pointing out that spermine and spermidine were originally found in sperm, hence the names. Just as putrescine, a precursor of the polyamines (spermidine and spermine) was first found in putrid material and cadaverine was first found in cadavers. But since the original observations, the polyamines have been found in most all cells.
(edit: except the cadaverine)

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Postby dignan » Mon Jan 15, 2007 12:08 pm

Wesley, just out of curiosity, do you get people in the autoimmune field rejecting your theories with detailed explanations of why they don't think it's worthwhile, or is it more that you might be on to something, but they have a lot of other theories to work on / fund that are just higher priority?
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Postby Lyon » Mon Jan 15, 2007 12:20 pm

Good question dignan.

Hello Wesley, I don't have the links on hand but I've read that researchers are looking into the genome of people with MS....looking for genes specific to MS.

I'm not arguing that what you're saying doesn't seem sensible (in fact I'd be lying if I said I have more than a tenuous understanding) but wouldn't what you mention stick out like a sore thumb when those people are looking through the genome?

Bob
Last edited by Lyon on Mon Jan 15, 2007 1:13 pm, edited 1 time in total.
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Postby BioDocFL » Mon Jan 15, 2007 1:08 pm

I think many researchers are focused on the immune system as being the main culprit. And many are focused on a genetic cause, expecting to find one or a few specific genes. So when someone like me comes out with a theory that differs from the immune system cause and differs from a genetic cause, then it is an uphill battle. They might consider my ideas way off but no one has said that so far, or pointed to why they would feel that.
I do not get any specific criticisms so that is why I keep putting the ideas out there, hoping to get feedback, pro or con. There are not many forums to discuss the ideas and usually discussions are within the context of someone's published findings. I am in cancer research and don't get to autoimmune type meetings. I would like to go and present the theory and take whatever heat I get.
My ideas are built around epigenetics (I did my PhD on histones and DNA packaging), X chromosome inactivation (also epigenetics, I did a post-doc on this), and polyamines (worked in this area too as a post-doc). I have been reading about lupus for 30 years now and got into biomedical research 17 years ago so I could work on these ideas as well as others. Now I am in drug discovery in cancer research since I was able to get involved in polyamine research that way. Hopefully there will be carry-over on the drugs we find. We just put in a patent on one potential candidate for inhibiting S-adenosylmethionine decarboxylase, which is involved in polyamine synthesis. It's a long way to develop it into a drug though, and it would be towards cancer therapy first.
I'll certainly admit that my ideas are very complicated, but then so are the autoimmune diseases. Not any easy answers so far. I will also admit that I could be wrong, but that's what theories are about, refining them until they fit tightly or are proven completely wrong. I just see too many things pointing to polyamines and epigenetics in autoimmune diseases like lupus and I think there are probably similarities among the autoimmune diseases so we should try to compare the research on the diseases.
I don't have MS or lupus and don't know anyone personally who does so I have no motivation personally other than curiosity about figuring out these diseases. In the meantime, I'm keeping my day job as they say.

Dignan, I think you hit it with the point about others having higher priorities as far as their own research and committed funding.

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