HPA Axis and MS

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

Postby OddDuck » Sat Feb 12, 2005 10:47 am

Ok.........I'm dying laughing. I've just zoomed ahead. My neuro at Vanderbilt is gonna love this, though. I'm suddenly at the same place they are! (re infectious diseases, gene transcription, etc. as it relates to causal relationships in MS.)

Wesley, this publication will be ESPECIALLY interesting to you, as it connects genetics with SLE AND MS, etc. http://www.jimmunol.org/cgi/content/full/169/1/5

In any event, I am now going back to "treatment" of all this, instead of causal relationships again.

:wink:

Deb
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Postby BioDocFL » Sat Feb 12, 2005 1:11 pm

So the article was saying that there are similarities in gene expression between RA and SLE and there similarities between type I diabetes and MS in the cells they looked at. Again, were the cells initiating the problem or responding to a problem in other cells. It seems like they are responding. The question remains: what is the expression pattern in pancreatic cells in type I diabetes, in chondrocytes in RA or SLE, and in oligodendrocytes, neurons, astrocytes, etc. in MS? That is the comparison I would like to see. Also, some kind of comparison on the percentage of cells with sporadic chromosomal abnormalities in those different tissue types. What is going on in those few cells at the center of an initiating lesion that is different than the other cells in the same tissue that don't get attacked by an autoimmune reaction? Is it that they are in a position that makes them more accessible to antibodies just leaving the blood flow, or perhaps a locally placed T cell that goes haywire and recruits a reaction against its neighbors? Baffling, bewildering, and befuddling.

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Postby OddDuck » Sun Feb 13, 2005 6:02 am

Yep, I'm with ya, Wesley!

That's why I gave up right then. About the time I really get deep into something is about the time I have questions that require the assistance of a lab (and staff). And the way I am, if I can't get right to it, I get frustrated.

Man, don't you wish we could ask these kinds of detailed questions directly to a panel of behind the scenes MS lab researchers and have them answer, etc.? Have a brainstorming session?

For instance, can you IMAGINE what would come of a brainstorming session with you, Robin, Sharon and myself, for example? Oh, man!

I have posed my initial question about why (or whether there has been any hypotheses) there is HPA hyperactivity without involvement of ACTH to a couple of people, but there is no telling if I'll get an answer.

And I had started thinking the same as you! WHAT causes "specific" cells in specific areas of the brain like that to be attacked? Why mainly in the hypothalamus? That's why I started targeting specific viruses which may have for some reason "attached" itself and/or "mutated" (I call it) in the hypothalamus. The problem is, that didn't really lead anywhere, either, but it's just the "easiest" and most logical explanation.

For some reason, though, I immediately just came back to gene transcription being the culprit, influenced BY something "genetic".

Yes, I re-read that publication, also and saw the diabetes and MS similarities. That explains, also, or should I say supports why a TZD (for diabetes) helped progressive MS so much (in preliminary studies). And a TZD is actually mild "gene" therapy.

Deb

EDIT: I gotta say, it does come around to something "epigenetic", doesn't it?
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Postby OddDuck » Sun Feb 13, 2005 6:17 am

Oh, yeah...........Wesley, have you run across the research that Dr. John Richert (the new VP of Research for the NMSS) has been doing regarding SP3? Dr. Richert is/has been doing extensive research on SP3 gene transcription expression in MS (or more to the point, the lack thereof of activation of SP3 in MS). He found that MSers do not have SP3 activation (which also explains why there is a difference between twins).

The theory he throws back into everything is toxins or environmental influences which causes the lack of SP3 activation.

I think I'll go look into that one for a bit - especially WHERE SP3 transcription takes place. If it is the hypothalamus, I think I'll croak!

Deb
Last edited by OddDuck on Sun Feb 13, 2005 9:06 am, edited 1 time in total.
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Postby OddDuck » Sun Feb 13, 2005 6:38 am

Wesley! Get this!

It has to do with hypertension, BUT...........look. Epigenetics, endocrine AND SP3 transcription, all roled into one. Hmmmmmmmmmmm.........

Ok........could you explain again, Wesley, what DNA methylation is and what causes it? You can get the full article at:
http://www.pubmedcentral.nih.gov/articl ... d=15489962

Deb


J Clin Invest. 2004 Oct;114( 8 ):1146-57. Related Articles, Links

Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression.

Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM.

Department of Nephrology and Hypertension, University Hospital of Berne, Berne UNK 3010, Switzerland.

The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) is selectively expressed in aldosterone target tissues, where it confers aldosterone selectivity for the mineralocorticoid receptor by inactivating 11 beta-hydroxyglucocorticoids. Variable activity of 11 beta HSD2 is relevant for blood pressure control and hypertension. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for the rigorous control of expression of the gene encoding 11 beta HSD2, HSD11B2. CpG islands covering the promoter and exon 1 of HSD11B2 were found to be densely methylated in tissues and cell lines with low expression but not those with high expression of HSD11B2. Demethylation induced by 5-aza-2'-deoxycytidine and procainamide enhanced the transcription and activity of the 11 beta HSD2 enzyme in human cells in vitro and in rats in vivo. Methylation of HSD11B2 promoter-luciferase constructs decreased transcriptional activity. Methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt, and nuclear factor 1 (NF1) diminished their DNA-binding activity. Herein NF1 was identified as a strong HSD11B2 stimulatory factor. The effect of NF1 was dependent on the position of CpGs and the combination of CpGs methylated. A methylated-CpG-binding protein complex 1 transcriptional repression interacted directly with the methylated HSD11B2 promoter. These results indicate a role for DNA methylation in HSD11B2 gene repression and suggest an epigenetic mechanism affecting this gene causally linked with hypertension.

PMID: 15489962 [PubMed - indexed for MEDLINE]


EDIT: Ok, I'm reading it. Oh my goodness, there is our "cortisol" connection again.

SECOND EDIT: Oh, my, my, my. One of their references (footnote 3) leads you to an article about glucocorticosteroids, with IL1b and TNFa, AND PLA2 (Canada found a direct connection regarding cPLA2 and demyelination.

All of which centers now around epigenetics. Some of their references lead you to cancer research, also.

Wesley, by golly, you just might be onto something yet!!!

Oh heavens! Their footnote number 29 takes you to an article that connects all this with P53 and cAMP! This can be directly traced to MS now.

So far, until Wesley chimes back in here about methylation, all I can find is reference to "diet". Which then anything extrinsic (such as toxins, etc.) could influence this. Ewwwwwww......... This is WAY too broad!
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Postby OddDuck » Sun Feb 13, 2005 7:44 am

Ok..........I'm seeing how this possibly will pertain to MS! And note, there is my mention of the complexities of IL4 (i.e. previous threads and initial narrative on desipramine).

Interesting.........

Deb

T-cell dna methylation declines as we age and is likely a cause of autoimmune disease (Yung et al. 1995).

....

Inherited defects of the methylation process would be expected to occur in humans and might lead to genomic instability during embryonic development or later in life. Later expression of the defect might predispose to a variety of malignant neoplasms. If activation of transposons could not be prevented during early embryogenesis, affected individuals might suffer new mutations that affect most or all cells of the embryo proper. Different mutations would be expected in different individuals who inherit the methylation defect, and various affected members of a single family might exhibit different new dominant diseases. http://www.csu.edu.au/learning/ncgr/gpi/jclub/9712/Index.html

....

http://www.qimr.edu.au/research/topics/ ... ation.html

DNA Methylation

Changes in gene expression that result in aberrant cell behaviour are the hallmark of a cancer cell. Contained within the human genome of DNA are thousands of CG dinucleotides. These are subject to a chemical modification called 'methylation', a process that can inhibit the expression of a gene. DNA methylation has many functions in normal cells, including suppression of 'tumor causing' genes and regulation of tissue specific genes. Recently DNA methylation has been shown to play a role in the initiation and progression of cancer cells. Adverse DNA methylation has been shown to inactivate tumour suppressor genes, promote chromosome instability and lead to increased mutations in the genome. These may all lead to cancer. Scientists at QIMR and around the world are trying to find out what turns such a normal mechanism of cell regulation into an initiator of cancer and how to stop or reverse the process.

QIMR Scientists are investigating how DNA methylation determines gene expression in the following research areas:

• Control of cytokine expression

• Regulation of membrane receptors
• Genomic imprinting

Immunoregulation
Lab Head: Professor Anne Kelso
anneK@qimr.edu.au

Our laboratory is interested in the development and control of specialised functions in T lymphocytes, especially their expression of genes for cytokines and mediators of cytolytic function. Our work on the behaviour of single T cells during primary immune responses has given us the following picture of early events in T cell specialisation.

Naive T cells have the flexibility to express different cytokines depending on the signals they receive during activation and many retain this flexibility through extended cell division. Individual patterns of cytokine expression are highly diverse, even within activated T cell populations with interferon-y or interleukin-4 biassed cytokine profiles. These biases therefore reflect a population average rather than a homogeneous cellular response. Regulatory signals, such as IL-4 itself, alter the probability that certain genes are expressed in a given cell, rather than acting in an absolute manner. Like cytokines, the mediators of cytolytic activity, perforin and granzymes, are differentially expressed in individual T cells. The T cell pool therefore comprises cells with striking functional flexibility so that population shifts in gene expression patterns can achieve a focussed response to a pathogen.

A major interest in the last year has been the regulation of cytotoxicity and cytokine profiles in newly-activated CD8 T cells, especially under the influence of IL-4. In the absence of this cytokine in vitro, and during influenza virus infection in vivo, we find that most effector T cells express one or more of the mRNAs for perforin, granzymes A and B, and IFN-y. Very few express IL-4 itself. Primary activation in the presence of IL-4, however, leads some naive CD8 T cells to develop into effector cells that express both IFN-y and IL-4 but display minimal cytolytic activity. Investigation of the molecular mechanisms that underlie this functional impairment suggest that IL-4 exerts dual actions, limiting both the recognition and lysis of target cells by reducing surface CD8 expression and perforin and granzyme production, respectively. An important next step is to evaluate the significance of this differentiative pathway for T cells when IL-4 is present during an immune response in vivo.


The last article posted above mentions the influenza virus. That's where I stopped when I said earlier that I had gotten to the place that Vanderbilt was at. I found the influenza virus as (one) of the extrinsic factors that might explain the reasons behind the continuing attack on the hypothalamus in progressive MS.

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Postby BioDocFL » Sun Feb 13, 2005 10:36 am

We're in the last stretch of getting our ovarian cancer grant application completed so I have to go to work today, and miss the Pro-Bowl game (football), but I can give a quick description of the DNA methylation. Also, bear in mind that histones around which the DNA is wound can also get methylation and both of these types of methylation can add to gene silencing.

DNA is made up of bases: adenosine, guanosine, cytosine, and thymidine or A,G,C,T. It is in two parallel strands and, between the strands, one strand will have an A and the other strand will have a T across from the A. G is across from C. So the DNA content always has A:T bases and G:C bases paired. The A content equals the T content and the G equals the C. The two strands are held together by hydrogen bonds (a hydrogen ion, ie. a proton, being shared by two atoms, one on each base). These hydrogen bonds can be broken easily temporarily to allow enzymes called polymerases to read the base sequences and make a duplicate mirror image copy. For transcription the duplicate is made in RNA, for replication, the duplication is made in DNA. This gets into sense and anti-sense terms for the gene and its opposite strand or transcript.

Okay, so when the two strands are bonded together, along the length of this double strand is a major and a minor groove. Think of an I beam girder where one side of the girder is slightly less open than the other side. The more open side, the major groove is typically where transcription factors, hormone receptors, etc. will read along the DNA until they find their particular recognition sequence. Then they bind tightly and start to work. However, if the DNA is methylated, there is a methyl group (one carbon with three hydrogens) sitting there in the groove attached to a cytosine base. It would appeat to block the recognition at that site. Also it gives some hydrophobicity there that alters the recognition. Enzymes called DNA methyltransferases can methylate DNA at C bases in some areas and the underlying gene or genes get silenced because the other enzymes can not recognize them. There are stretches called G-C islands typically near the start of genes. These are areas that are rich in G-C pairs and can be methylated leading to a stretch of methylated bases just at the start of the gene. This is very effective in shutting down the gene. Histones that are methylated too can add to this silencing. The chromatin (DNA and histones) can become somewhat insoluble with all this neutralization so it becomes less accessible. Histones are methylated at lysine and arginine residues which normally would have a positive charge making the histones soluble but the methylation reduces this positive charge, making it more insoluble, hydrophobic.

Methylation abnormalities are found in lupus. It is interesting that the article mentions procainamide because that was one of the first drugs determined to cause drug-induced lupus. It is normally given for high blood pressure or heart arrythymia (can't remember which). Hydralazine is the other best known drug for drug-induced lupus.

The methyl group used for DNA and histone methylation is from a molecule call S-adenosylmethionine or SAM. In polyamine synthesis one of the key initial steps is decarboxylation of SAM to produce dcSAM which is used to make polyamines. So there is a conflict between DNA/histone methylation and polyamine synthesis. In cancers (and I think autoimmune diseases) there is an increase in polyamine synthesis so there is a reduction in available SAM for DNA/histone methylation. This leads, in my opinion, to abnormal methylation patterns and the reactivation of genes because there is no longer the methylation to keep them suppressed.

Methylation is also involved in cell differentiation. As a cell develops from a precursor (stem cell or later), it shuts off some genes it will not need, such as a neuron shuts off its genes to make insulin, let the adrenal glands do that (or is it the pancreas? My memory is failing). In cancers, as the cells transform into continuous replication, they do not have time to methylate the continuously growing DNA and so there is not proper methylation. Cancer cells tend to revert to less mature cells. It can work both ways though, they can methylate the wrong sites too. When DNA replicates, the existing methylation pattern gets split between the two new strands and two old strands. An old strand (methylated) is paired with a new strand (not yet methylated). There are particular DNA methyltransferases to deal with this hemi-methylated DNA and do further metylation. This is fairly efficient. Then there is de novo methylation, where there is no existing pattern to copy. De novo DNA methyltransferases handle this but you can imagine it is less efficient and prone to errors.

Another thing to ponder, eukaryotes (humans etc) methylate cytosine bases and have histones. Prokaryotes (bacteria) methylate adenosine
bases and don't have histones. So as a defense, cells will usually methylate all foreign DNA (what they think is foreign anyway). This could potentially shutdown transcription of the bacterial DNA (or viral DNA) and protect the cell. So the bacterial or viral DNA could be shut down for now but it could go into a latent state and become active later when there is a disruption of the chromatin and a loss of methylation.

Also, DNA in alternating G:C sequences that is methylated is the best stretch for formation of Z-DNA (left handed coiling of the double strand). It is still under investigation what the significance of Z-DNA is in cells. Apparently it can have some effect on transcription rates. Autoantibodies against Z-DNA are found in lupus, and the antibodies bind better when polyamines (especially spermine) are around to help stabilize the Z-DNA structure.

Guess which enzyme I am working on now? S-adenosylmethionine decarboxylase (SAMDC), the enzyme that reduces SAM to dcSAM at the start of polyamine synthesis. There are some known inhibitors that have been in clinical trials and seem to be effective (cgp486 also called SAM486A). We are doing virtual screening and have come up with many more compounds that could inhibit SAMDC (cpg486 only ranked #92 on our last run). But we need to verify these drugs with actual enzyme kinetics and tissue culture and mouse testing to determine the toxicity problems they might have. SAMDC is important in cancers and perhaps in autoimmune diseases as I have been saying. I think I'm in about the best place I could be to work on my ideas and, if we get the ovarian cancer grant, you ain't seen nothing yet!

Wesley

Oh, also SAM is a precursor to some of the neurotransmitters. So reduce SAM in some cells and you could be hampering synthesis of those neurotransmitters.

edit: There are some proteins, like MeCP2, that bind DNA methylated sites and add to the shielding of the site. There are even diseases where there is a difficiency of the protein, which happens to be from a gene on the short arm of the X chromosome.

Also, everything I said there are of course exceptions. There are probably a few genes that can become more active when sequences near it are methylated but that would be the exception. Those cases might have to do with nucleosome placement or other genes running in the anti-sense direction that normally override them.

Also, homeoboxes are sites that control a group of genes. Methylate the homeobox and it shuts off a group of related genes. These are often in relation to cell differentiation.
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Not Very Scientific HPA Hyperactivity Information

Postby Shayk » Sun Feb 13, 2005 3:26 pm

Hi Deb, Bromley and Wesley

I take a very simplistic, rather macro and definitely not a scientifically informed approach to HPA hyperactivity. So, Deb and Wesley, I have to leave you to your expertise and stick to posting some general information. I’m lucky I was able to figure out that HPA hyperactivity tended to correlate with high levels of cortisol. :)

Deb asked:
Sharon, you're our hormone expert.......what have you found about this?):
did you find the ACTH paradox, also? What do you make of that?


First, I want to be really clear I am not an expert on hormones or MS. I started learning about hormones and MS at the same time since I associated my diagnosis with the radical decline and/or absence of hormones at my geezer age. :lol:

I didn’t find the ACTH paradox and don’t know what it is. I have read there are several ways to measure cortisol, the ACTH challenge test is only one.

Deb said:

In an odd way, it does make sense to discover that ACTH stays within normal limits in MS, though, because if ACTH was involved at all in MS, then the disease itself would either present itself as Addison's or Cushing's, not MS. Right? And for some strange reason, we don't even find Addison's or Cushing's as co-existing with MS!? How odd!!!


A possible explanation for why Addison’s or Cushing’s don’t “co-exist” with MS

My lay person perspective on this is taken from a book, Adrenal Fatigue, the 21st Century Stress Syndrome, by James Wilson, who notes that
“So called “normal” lab values for cortisol include all but the most extreme values”, too much cortisol, more than 2 standard deviations above the mean, results in a diagnosis of Cushing’s Syndrome, and too little cortisol, more than 2 standard deviations below the mean, results in a diagnosis of Addison’s disease.


From what I’ve read, there aren’t any other diseases recognized with either too much or too little cortisol. This made me wonder if MS then might be a disease of too much cortisol in PwMS that’s simply never been “diagnosed” or “detected” because routine lab tests for cortisol would be reported as normal in PwMS even if their cortisol levels were, for example, 1.5 times above average.

According to Harrison’s Principles of Internal Medicine, 14th ed. Vol. 1. McGraw-Hill, p 1970, 1998).

“Most hormones have such a broad range of plasma levels within a normal population. As a consequence, the level of a hormone in an individual may be halved or doubled (and thus be abnormal for that person) but still be within the so-called normal range.”


Bromley, to the extent that HPA hyperactivity reflects high cortisol levels, here’s what I’ve found in a book entitled: The Cortisol Connection, by Shawn Talbott, who is a nutritionist. From page 33, Table 4.1:

Metabolic and Long-Term Health Effects of Elevated Cortisol Levels

Metabolic Effect (Cortisol-Induced)

Increased appetite, accelerated muscle breakdown, suppressed fat oxidation, enhanced fat storage

Elevated cholesterol and triglyceride levels

Elevated blood pressure

Alterations in brain neurochemistry (involving dopamine and serotonin)

Physical atrophy (shrinkage) of brain cells

Insulin resistance and elevated blood-sugar levels

Accelerated bone resorption (breakdown)

Reduced levels of testosterone and estrogen

Suppression of immune-cell number and activity

Reduced synthesis of brain neurotransmitters

In one paragraph he says the same thing a different way (sort of artsy Bromley :wink: ):

Over the long term, elevated cortisol levels can be as detrimental to overall health as elevated cholesterol is for heart disease or excessive blood sugar is for diabetes. Aside from that, elevated cortisol levels make you fat, kill your sex drive, shrink your brain, squelch your immune system, and generally make you feel terrible.


The Cortisol Connection book does go into stress and cortisol for us lay people, and does present general recommendations for controlling cortisol levels: the SENSE program. S= stress management; E = exercise; N= nutrition; S=supplements; and E = evaluation.
The goal is to have a healthy level of cortisol, not too much and not too little. The lab that did my saliva hormone testing recommended I read the book because of my high cortisol levels.

Now, you know I can’t do a post this long without mentioning hormones. :) So, on to other hormones and the adrenal gland.

The research article Sex Hormones Modulate Brain Injury in MS found worse MRI outcomes in 32 year olds with RRMS in sex hormones that are apparently primarily produced by our adrenal glands. That is too little and too much testosterone in women and too much estradiol in men was associated with worse outcomes.

The book I mentioned earlier on Adrenal Fatigue makes the point
that both male and female hormones are made in the adrenals of each person, regardless of gender.

In males, the adrenals provide a secondary source of testosterone and are the exclusive source of the female hormone estrogen (referred to collectively as estrone, estradiol and estriol.)

In females, the adrenals provide a secondary source of estrogen and progesterone, and are the nearly exclusive supplier of testosterone.


Interesting…..that’s all I can say.

I’m still voting for balanced hormones (including cortisol) to help manage MS.

Sharon
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Postby OddDuck » Mon Feb 14, 2005 4:55 am

Hi, Sharon!

Great post! Thank you! And I totally agree with you, just from what little I have found so far!

This whole avenue needs to be researched much more.

Not every type of MS (especially progressive MS) involves immune system "inflammation".

I still wonder if MS hasn't been used as too much of a "catch-all" diagnosis for MANY different unnamed diseases (albeit with the same exhibition of symptoms).

Deb
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Postby OddDuck » Mon Feb 14, 2005 12:12 pm

Ok.....so far, we have found continuing "lesions" in the hypothalamus in progressive MS. My original thought was that some dysfunction was causing the lesions in the hypothalamus, NOT that lesions were causing the HPA axis dysfunction.

I am going to be bold enough to suggest that I am correct. I have found in my research that a consistent high level of corticosteroids in the body due to HPA axis dysfunction (as we see is evidenced in progressive MS) CAUSES lesions! Hence why the lesions are concentrated in that one section of the brain.

And my hypothesis that progressive MS may at least be helped and/or some of the disability be able to be slowed down by taking desipramine (perhaps even in some type of combination treatment, also) might yet prove to be correct.

<shortened url>

The physiological presentation of progressive MS is almost identical to the physiological presentation of clinical depression. Which we have heard many times, i.e. how often or how closely MS and depression are (as disease pathogeneses, not purely symptomatic presentation). You need to focus on the biological dysfunction, not the "emotional" disruption that the term depression connotates.

This publication explains how desipramine is cytoprotective in the very circumstances that is being shown in studies to be prevalent in progressive MS.

Deb
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