Polyamines

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

Postby BioDocFL » Wed Oct 13, 2004 10:24 am

I doubt I can get away since we are having a meeting with our collaborators on the 18th-19th. That's what has me busy today, getting ready.
Wesley
User avatar
BioDocFL
Family Elder
 
Posts: 251
Joined: Wed Aug 11, 2004 3:00 pm
Location: Florida

Postby OddDuck » Wed Oct 13, 2004 11:18 am

Ok....I just thought I'd mention it.

It's in the evening, though. I think it starts at around 6 p.m. EST and runs until about 8:30 p.m. or so (just in case you find you might still fit it in).

:P

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby OddDuck » Thu Oct 14, 2004 4:41 am

Wesley,

In attempting to learn more about polyamines, I found this on the Lund University website:


"....The biosynthesis of polyamines is increased by a great variety of physiological growth stimuli, and polyamine deficiency results in an arrest of cell proliferation, which can be reversed by supplementation with external polyamines. Polyamine deficiency can also, under certain circumstances, result in programmed cell death or apoptosis. ...

...In most cell types, the biochemical characteristics of programmed cell death include the activation of endogenous calcium and magnesium dependent endonucleases, leading to fragmentation of the chromosomal DNA. Previous results from our and other laboratories indicate that DNA is destabilized in polyamine-depleted cells. This results in a greater vulnerability of DNA to nucleasal attack. Because DNA is known to become degraded during programmed cell death, we have begun to investigate if polyamine degradation plays an active part in the process."

So, correct me if I'm wrong, Wesley, but I'm thinking that in your last post, you might be saying the same thing as Lund? It's not "overexpression" of polyamines, it might be "underexpression" which then leads to apoptosis in MS?

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby OddDuck » Thu Oct 14, 2004 5:09 am

Ok, I'm starting to put where polyamines might figure into apoptosis in MS, but it's still a loose one at this point. BUT......it's there.

Folks may find the following items interesting.

Deb

********************

Published online July 14, 2003 as 10.1083/jcb1622iti1.
This Article

PubMed

Articles by LeBrasseur, N.

© The Rockefeller University Press, 0021-9525/2003/7/166 $5.00
The Journal of Cell Biology, Volume 162, Number 2, 166-166
--------------------------------------------------------------------------------
In This Issue
Polyamines in inflammation
--------------------------------------------------------------------------------

LPS-induced neurodegeneration (circled, top) is reduced in the absence of polyamines (bottom).

Results on page 257 by Soulet and Rivest implicate polyamines in controlling immune responses in the brain. Their results suggest that polyamine synthesis, if left unchecked, can cause damaging inflammatory responses reminiscent of neurodegenerative disorders.

Recognition of bacterial and viral pathogens by microglial cells, the brain's equivalent of macrophages, elicits a cascade of gene expression leading to inflammation. Little is known about what regulates this response, but the group banked on an involvement of polyamines because the rate-limiting enzyme in their biosynthesis, ODC, is induced by the bacterial toxin lipopolysaccharide (LPS). They find that polyamines are pro-inflammatory molecules that regulate neuroimmune responses in mice.

The authors inhibited polyamine synthesis by feeding mice a chemical that blocks the ODC active site. The drug prevented the activation of pro- inflammatory genes, including Toll-like receptors and cytokines. In contrast, injection of the polyamine spermine amplified the induction of these genes beyond that caused by LPS alone. Polyamines are organic polycations that interact with negative molecules, such as DNA and proteins. Although normally sequestered in an RNA-bound form, free spermine might activate transcription by binding to DNA or to transcription factors.Neurodegeneration can be modeled by blocking glucocorticoids, which normally down-regulate neuroinflammatory responses. The authors find that, when glucocorticoid receptors are blocked, preventing polyamine synthesis protects mice from neurodegeneration induced by LPS. If polyamines are also responsible for neurodegenerative disorders such as multiple sclerosis, an ODC-blocking drug similar to that used on the mice might be useful in humans.

Nicole LeBrasseur

lebrasn@rockefeller.edu

Related articles in JCB:

Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system
Denis Soulet and Serge Rivest
JCB 2003 162: 257-268. [Abstract] [Full Text]

*********************************************

Here's a website on the immune system that I found fascinating: http://xoomer.virgilio.it/medicine/immunityinnate.html

I also found mention in this website of several of the things I have posted here before:

PTX3 / TSG-14 : it prevents cell remnants from being captured by APCs, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues. Up-regulated by IL-1b.

Cell-autonomous cell death : viral infection or excessive DNA damage trigger apoptosis in the affected cells through PKR- and p53-dependent pathways, respectively.



Diagram of apoptosis:


http://xoomer.virgilio.it/medicine/apoptosismap.htm
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby BioDocFL » Thu Oct 14, 2004 7:54 am

OddDuck,
So now maybe you're seeing the two-faces of polyamines: a deficiency of polyamines can lead to apoptosis (possibly due to the loss of polyamine influence on calcium flow), and an increase in polyamines can lead to inflammation, which could include attacking aberrant cells and material. Thus the need to control their levels. This is what I have struggled with for years in trying to develop a theory on autoimmunity. It can make you paranoid thinking of a tangent to the hypothesis but then thinking there are contradictions. Just too many unknowns on polyamines still. You will also notice that often they are mentioned as a group and not broken down into spermidine effects, spermine effects, acetylspermidine effects, and acetylspermine effects. One thing is that it has been difficult to determine levels in vivo at different locations in the cell for spermine vs spermidine vs acetylspermine vs acetylspermidine vs putrescine: nucleus vs cytoplasm vs external, membrane bound vs DNA/RNA bound vs free. Add to that the changes due to cell cycling (up in S phase and mitosis), hormone stimulation (estrogen, gluccocoticoid, etc.), and stress response (UVB light, viruses, amino acid analogs, toxins, etc.).
This is why I am thinking of fragmentation in a cell disrupting epigenetic control, and possibly passing fragmentation and perhaps uneven chromatin distribution along to daughter cells that could lead some cells to underexpress polyamines leading to apoptosis quickly and other cells to overexpress polyamines disrupting the normal cell functioning locally and provoking inflammation. Perhaps cells can not pull in or expel polyamines efficiently to compensate for disrupted expression internally. The chromosome aberrations in MS reported by the Italian group I mentioned, I am wondering if there were alot of cells with X chromosome abnormalities that they did not consider because those cells had already gone through apoptosis, ie. for every X abnormal cell they saw, perhaps there was another already destroyed giving them a lower count on X abnormal cells.
As far as inflammation, autoantibodies in lupus against DNA appear first in a flareup of lupus, before other autoantibodies (like anti-Ro, anti-La), even before the patient shows symptoms. In lupus >90% of patients have anti-DNA Abs, whereas anti-Ro, anti-La I think are less than 50% of patients. The DNA is mostly if not entirely endogenous in origin (not from a pathogen). If you take anti-DNA autoantibodies from a lupus patient and mix with DNA and then check for DNA that has bound, and then as a second experiment you do the same but premix the DNA with polyamines, the autoantibodies pull down alot more DNA in the presence of polyamines than without, suggesting a possible role for polyamine/DNA interactions in the initial reaction of the immune system to the DNA. Also, DNA stabilized into Z-DNA form by polyamines, nickel ions or some other agents seems to bind better to some of the autoantibodies. I think the DNA is often the first target in lupus and later, by epitope spreading and guilt by association, the histones and other proteins become targets. There is something different about the DNA, even though it is endogenous in origin. I'll get into that later because it gets into potential alternate replication sites and reverse transcriptases. Probably the most interesting part of the whole hypothesis because it ties together many of the lupus autoantigens.
I have alot to say about this area, particularly relating polyamines and DNA to lupus but I probably can't write much about it until this weekend. My feeling is that some problems with polyamine/DNA interactions may be occurring in MS but the immune system can not access it and react to it as easily as in lupus. Other aberrations become the priority in MS such as perhaps alterations in myelin.
Anyway, remind me that I owe you posts on the hypothesis relating to: DNA/polyamine interactions, lupus autoantigens, reverse transcriptases, chromatin packaging, probably some other areas I've forgotten already. I don't know if I'll be able to write the long version of my article soon but probably from all these posts I can come back and organize them into a better order and tie them together into one.
more later.
Wesley
User avatar
BioDocFL
Family Elder
 
Posts: 251
Joined: Wed Aug 11, 2004 3:00 pm
Location: Florida

Postby OddDuck » Thu Oct 14, 2004 10:58 am

Wesley,

Ok....but here's right about the point where the connection with MHC (and chromosome 6) would need to be made. This part is crucial to integrating your theory with MS. If that is missing in any way, I'll bet you a million dollars that nobody in MS research will even listen to you. They have isolated that MHC, which involves self-recognition (and its associated chromosomes and genetic haplotypes) is definitely involved in MS. They have gotten that far for certain. (I'll paste below a layman's description of MHC). So, I was basically correct before when I said you would need to show a direct connection at some point between your hypothesis and MHC, especially MHC II. (I only just now confirmed it to myself, is all. HAH!)

If there is fragmentation or epigenesis such as you suggest going on, it's at that point. Involving chromosome 6. (Dr. David Hafler is the best in the field as far as that goes. Refer to his findings. I think his findings and yours are real close to meshing. There's just a small "gap", shall we say, in your thinking and his. But you may be able to bridge that gap somehow.) I can sort of "see" it, but I can't verbalize it. That doesn't mean I'm convinced that it's a CORRECT hypothesis or anything, because as you said, it would require a lot more than just hypothesis. And proving it, though, might be something else altogether, but I can't even begin to talk intelligently about that part.

Another thing I've realized is that (in layman's terms), there are sort of different definitions of the word "autoimmune". During my discussions with Dr. Sam Hunter, he used to like to play word games with me. He'd say only one word, and then say "you're a smart woman.....figure it out". Going back to my and Sam's "discussions" regarding whether or not MS was actually an "autoimmune" disease, he'd simply say DEFINITIVELY "Yes, it is." I'd say "maybe not". He'd grin and say "Oh, yes it is". And then he'd tell me to figure it out. LOL

Ok......In talking with you Wesley, and doing further research, now I see what he was telling me. Sam was using the word "autoimmune" to mean "self recognition process". Ok........the self-recognition physiological process, i.e. the BIG picture of it, also includes all of those processes that occur WAY before the "immune system", as we think of it, gets triggered. Which MHC involves self-recognition. (That bugger! THAT'S what he was wanting me to figure out! :lol: Sam found that out himself YEARS ago. He did a lot of the initial research on MHC! Good thing I used his own research when I did mine! He asked me where I got some of it, and I told him that a lot of it was his own! He grinned about that one.) BUT.....like I mentioned previously, that starts getting into "gene therapy", even if it is therapy directed at polyamines, ptx3, p53....any of those. You are still basically talking "gene therapy"; even to prevent what you are talking about might be happening, Wesley. That's where it gets tricky!

So....in the meantime, the best focus that they can do at the moment is trying to stop the cascade of events that happens later on in the process. They are simply attempting to interrupt the process at a later time in the "domino effect", as I call it, when there is less risk to the patient. You can either correct or interrupt the process earlier on (such as what you are suggesting would probably need to be done), or at any point subsequent. Just like dominoes. You can interrupt the downfall of dominoes at any point (before the end) IF you can interrupt one of the dominoes anywhere in the line.

No WONDER Sam was interested in my research on desipramine! I hit something even better than I realized. I did what I am suggesting to you, Wesley. I found the connection of desipramine being a mild "gene therapy" that helps to prevent the changes in DNA fragmentation and its beneficial effects on MHC. (hmmmmmmmmm.....I wonder what Sam will do with my research now. LOL) I understand now, also, why he was shocked at what I had found, why he said "But we can't prove it". We didn't have a LAB! Not one the size you would need in order to do the appropriate research on it! And I won't go into how you can't just walk into a University and say "Hey, can I borrow your lab?" AHA! :idea:

Well, Wesley, I'm definitely interested in hearing more. This is getting good. And I think I'm more correct than ever. Dr. Sam Hunter would be your "guy" if you can get to him. I did send him an email and told him about you, by the way (but of course, I couldn't say much about you....how much do I know?), and that you MIGHT look him up when he's in Tampa next week. I can't guarantee that he'll listen to you, or even give anybody the time of day, but he's your best bet. He's about the only one who's open enough to consider new ideas. If he seriously considered mine (and still does), then he might be open to considering yours. The problem is, also, that he's spread so thin right now. That's why I said, also, that not only would your theory need to be strong, but Sam has a PhD in pharmacology/toxicology and is an immunotherapist and he's concentrating right now on MS treatment, so an additional avenue to capture his interest would be to provide some valid speculation on what current or new type of therapy might apply, also. (Maybe desipramine! HAH!) I still think that at least on paper, desipramine is almost taylor-made for MS. Sam did, too. :wink:

In any event, I look forward to hearing more from you when you have time.

Deb

The major histocompatibility complex
30/7/03. By RT
A cluster of genes essential to the immune system.

The major histocompatibility complex (MHC) is a large cluster of genes found on the short arm of chromosome 6. The complex spans four million base pairs of DNA and contains 128 genes as well as 96 pseudogenes (non-functional gene remnants). Many, but by no means all of the genes in this complex play important roles in the immune system.

Traditionally, the MHC is divided into the class I, II and III regions, each containing groups of genes with related functions.

The class I and II MHC genes encode human leukocyte antigens (HLAs), proteins that are displayed on the cell surface and define an individual’s tissue type (see article on tissue matching). There are many possible tissue types in the population because each HLA exists as a large number of varieties. Everyone’s immune system is tolerant of its own HLAs, but if foreign HLAs are detected then the cells displaying them are attacked and destroyed. This is why the body rejects grafts and transplants from donors that have not been matched for tissue type.

The class I and II MHC proteins also perform the important function of antigen presentation. This is how the immune system finds out what is happening inside our cells even though it can only survey them from the outside. Proteins inside the cell are broken into short fragments and displayed as peptide antigens by MHC proteins on the surface. This helps the immune system to discriminate between normal (self) antigens and those that are foreign and potentially dangerous.

Class I MHC proteins are found on virtually all cell types and their job is to present fragments of proteins that are synthesized inside the cell. The peptide antigens presented in this manner are checked by killer T-cells, which have receptors for the class I MHC proteins. The purpose of this surveillance system is to identify abnormal body cells, such as those infected with viruses or those that have turned malignant. Such cells will display unfamiliar peptide antigens, e.g. fragments of viral proteins, and are attacked and destroyed.

Class II MHC proteins are found only on immune cells such as phagocytes that engulf foreign particles such as bacteria. These cells are specially designed to present peptide antigens derived from such digested particles. The antigens are presented to helper T-cells, which have receptors for class II MHC proteins. The purpose of this surveillance system is to stop the immune system running out of control and attacking the body’s own cells. Only if the presented antigen is recognized as foreign by the helper T-cell is the phagocyte allowed to survive.

Class III MHC genes encode several components of the complement system, a collection of soluble proteins found in the blood that targets foreign cells and breaks open their membranes. Adjacent to the class III region is a group of genes that control inflammation. Further genes with various immune and non-immune functions are dotted throughout the complex.

The MHC shows a high degree of polymorphism (100 times higher than the genome average, i.e. a 10 per cent difference between any two unrelated individuals). Many of these polymorphisms appear to be associated with either increased or decreased susceptibility to a range of infectious diseases including malaria, tuberculosis, leprosy, typhoid fever, hepatitis and HIV/AIDS.

Defects in certain MHC genes lead to autoimmune disorders in which the body fails to recognize self-antigens. Examples of such diseases include multiple sclerosis, some forms of arthritis and diabetes, and inflammatory bowel disease.
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby OddDuck » Thu Oct 14, 2004 1:32 pm

Ok, in David Hafler's recent article that I posted yesterday, he also mentions the following:

"....Recently four pathologic categories of the disease were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T cell–mediated or T cell plus antibody–mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a vasculopathy or primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity (25). It was of interest that the pattern of pathology tended to be the same in multiple lesions from any single individual with MS. ...."

Ok..........humoral.........that rings a bell. I found a connection somewhere else regarding humoral response........what was it???? (Well, I did want Dr. Kirshner, who is now vascular, on my MS Research Dream Team...LOL) Ok, the other thing Hafler is saying is oligodendrocyte "dystrophy" (i.e. lack of nutrition). Both of these being "reminiscent of virus or toxin induced demyelination". Geez!! I'm back where I started! HAH!

Anyway, Wesley: Hafler has done a lot of MS research in connection with the X-chromosome, and if you haven't read his stuff yet, you might consider it.

Here is a possible item of interest:


http://www.jimmunol.org/cgi/content/full/170/2/1019

I also found what Hafler said in this article to be of possible interest to the general public. I haven't checked out the website he refers to yet, though.

http://jmg.bmjjournals.com/cgi/content/full/40/8/553

"....Furthermore, by linking gene expression data to existing databases containing functional annotations (such as GeneOntology at http://www.godatabase.org/dev/database/), it is possible to evaluate results from microarray experiments from a functional point of view. Identifying patient groups that are homogeneous at the molecular level, that is, by gene expression profiling, will be facilitated by the creation of large databases containing comprehensive expression data from a variety of tissues and pathological conditions. The importance of this latter goal has convinced and moved investigators and institutions to undertake major efforts to carry out the project and to make the databases immediately available to the public domain.85–88...."

In this article http://www.jci.org/cgi/content/full/105/7/977, Hafler footnotes this:

: Immunogenetics. 1993;37(3):204-11.

T-cell repertoire in a strain of transgenic C57BL/6 mice with the HLA-DRA gene on the X-chromosome.

Fukui Y, Esaki Y, Kimura A, Hirokawa K, Nishimura Y, Sasazuki T.

Department of Genetics, Kyushu University, Fukuoka, Japan.

We have established a strain of transgenic mice in which the HLA-DRA gene was integrated into the X-chromosome and the xenogeneic mixed isotype molecule, DR alpha E beta b, was expressed in a cell type-specific manner, although the transgenic DRA gene contained only 268 base pairs of the 5'-flanking region. The DR alpha E beta b molecules expressed in the transgenic mice functioned as major histocompatibility complex (MHC) class II to select T-cell repertoire, and to stimulate mixed lymphocyte reaction. In female transgenic mice homozygous for HLA-DRA (DR alpha-B6-F-homo) and male transgenic mice (DR alpha-B6-M), DR alpha E beta b molecules were expressed in almost all of the MHC class II Ab-positive cells. In contrast, the expression of DR alpha E beta b molecules in female transgenic mice hemizygous for HLA-DRA (DR alpha-B6-F-hemi) was found only in part of the Ab positive cells, and the proportion of cells expressing the DR alpha E beta b molecules varied due to random inactivation of one of the X-chromosomes. Clonal deletions of the T cells and mature thymocytes bearing Tcrb-V5 and Tcrb-V11, which are eliminated from the peripheral repertoire in mice expressing self-superantigen and MHC class II E molecules, were incomplete in DR alpha-B6-F-hemi as compared with those in DR alpha-B6-F-homo, and were correlated with the proportion of DR alpha E beta b-positive spleen cells. These observations suggested that the number of bone marrow-derived cells expressing DR alpha E beta b molecules was critical for clonal deletions of Tcrb-V5+ and Tcrb-V11+ T cells in the thymus.

PMID: 8420827 [PubMed - indexed for MEDLINE]


Man, I'm telling ya, I'm getting WAY out of my league! Phew! :? I'll stick to pharmacology.

Ok.....I'll hush up now and wait for Wesley's next post. :wink: Time to get back to polyamines.

Deb


EDIT: Well, wait a minute! Give all of the above, how in the world did Dr. Hunter and Dr. Hafler meet in the middle regarding the different patterns of MS? Hunter says "autoimmune" to them all no matter WHAT the causal relationship may be (virus, allergen, toxin, etc. - we talked about that, too), and Hafler acknowledges there are some forms of MS that probably should not be considered "autoimmune". I'm missing something there. LOL Well, maybe not. Still..........the common denominator of everything still boils down to MHC (self-recognition).

WESLEY: What is your definition of "autoimmune"? Perhaps we should clarify that real quick.
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby BioDocFL » Thu Oct 14, 2004 2:51 pm

It seems that one could call a disease as autoimmune if there is a reaction of the immune system to the body's own material. That reaction may have been started by an abnormality in the immune system, perhaps overexpression of a cytokine, or it may have been started by something originating from non-immune cells that the immune system interprets as foreign because that material, although endogenous, has something different about it, such as myelin that for some reason has a more positive charge overall because it is incorporating spermine into it in place of spermidine (don't know if that really occurs but it shows an alteration of endogenous material only). Histone and DNA complexes are endogenous in origin but perhaps the histones have been modified by peptidyl arginine deiminase, a naturally occurring enzyme. The arginine residues have been converted to cittruline. Again, I don't know how much if any that might occur in vivo but it is endogenous material that now presents alterred epitopes that the immune system may not have encountered on a regular basis before. Just calling something an autoimmune disease doesn't mean that it is immune system-driven, as the first scenario would be (cytokine example). It could be a response to alterred endogenous material, and therefore could be considered secondary to an earlier problem.
I don't know if there is a definition of autoimmune in there. I'll have to think about a good definition.
Another thing I was thinking about recently, I mentioned the quaking and jimpy mice that have neurodegeneration. I don't think they have an immune system response but I might be wrong. I was thinking though that they might tolerate abnormal endogenous material that develops because mice have a thymus around for a while after birth whereas the human thymus has pretty much atrophied at or soon after birth. The mouse immune system may be still learning tolerance and accepts the early onset of the neurodegeneration as normal. Just thinking out loud. So what if the quaking or jimpy mouse was thymeticized, thymiticized, ....how about if the mouse had its thymus removed at birth? I wonder if that would give it an autoimmune response when the neurodegeneration starts because it can no longer learn tolerance. I might be missing something there so I don't know how that would wind up.
As far as MHC and HLA, there are some subtypes that are found more often in lupus patients too. Usually you hear of peptides being bound and presented, not so much DNA, RNA but it is possible for them to fit in. Perhaps some MHC subtypes can bind DNA or RNA better than other subtypes, especially when there is an alteration in the epitopes due to excess polyamines around. I'm not very familiar with MHCs with regards to autoantigen presentation but I believe some of the MHCs can allow for more variation in the presentation, kind of sites of loose fit in the pocket while other portions of the antigen meet the fit criteria for that particular MHC pocket.
Anyway, time for my long commute home for the evening.
Wesley
User avatar
BioDocFL
Family Elder
 
Posts: 251
Joined: Wed Aug 11, 2004 3:00 pm
Location: Florida

Postby treez » Thu Oct 14, 2004 3:19 pm

You guys(and girls) went way over my head a long time ago. I wasn't told by Aaron I'd need my Ph.D. to read and post on this site

:)

OddDuck made a comment about giving the brain time to catch up.

Yah, me too.............see you in about 3 weeks :?

Just making fun with people talking about 10 feet over my head. No offense intended..........all in good fun

Treez
User avatar
treez
Family Elder
 
Posts: 128
Joined: Tue Jul 27, 2004 3:00 pm
Location: Michigan, USA

Postby OddDuck » Thu Oct 14, 2004 3:24 pm

Just calling something an autoimmune disease doesn't mean that it is immune system-driven, as the first scenario would be (cytokine example). It could be a response to alterred endogenous material, and therefore could be considered secondary to an earlier problem.


Actually, I think I got it!! (Man, sometimes I surprise myself! It's like learning a foreign language.....sometimes you can understand it before you can speak it.)

That's sort of what I was getting at. Dr. Hunter's "definition", then, would probably be similar to that. It boils down to simply "self-recognition", whether the immune system reacts or not. Both dysfunctions (inflammation or lack of inflammation) for whatever reason could still indicate "autoimmune disease", right? (Correct me if I'm wrong.) Ok............that would explain his goofy grin.

Thanks, Wesley, that makes sense.

Believe it or not, I'm following the rest of your post, too! Thanks for the mind "workout"......

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby OddDuck » Thu Oct 14, 2004 3:27 pm

ROFL!! Treez!!!

Hey, I know!! Remember, this is only this one "thread" out of this whole board that is so "deep". And like I said.........it's giving me a mind workout for sure!

Deb

P.S. It's getting clearer though. I probably make it worse with all my questions. :P It's like a half-finished novel now, though. I GOTTA hear the rest of Wesley's thoughts on this and the rest of his hypothesis. :D
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby BioDocFL » Thu Oct 14, 2004 5:05 pm

Treez,
Join in. I welcome questions of any type because I want to make sure I can explain things clearly. I know there are people with different exposure to biology so I need to go into more depth on some areas. Sometimes questions can point to things I don't understand well enough myself or perhaps I have wrong. Remember this is only hypothesis and it touches on alot of areas, many of which I have not studied much. I'm giving you folks stuff that I have been working on for at least 18 years so give yourself a little time to understand. However, I would recommend that you take an evening class in biology (just audit it) or maybe put yourself into a biology textbook, the more recently published the better.
The big problem I am having is finding the time to write out the bits and pieces as I have been doing here and also getting out answers to questions quickly. Hopefully I can spend more time this weekend but next week will be hectic too for me.
Wesley
User avatar
BioDocFL
Family Elder
 
Posts: 251
Joined: Wed Aug 11, 2004 3:00 pm
Location: Florida

Postby OddDuck » Fri Oct 15, 2004 4:21 am

Hey, folks.........do you think it's too late for me to go to college now? 8O LOL I never went because I could (and did) read a lot of textbooks on my own (I used to say if Abe Lincoln could do it, so could I.........and save a lot of money that I didn't have.) I have taken a few medical classes in the past, though, even though I'm a paralegal. Legal liability cases required someone who could read the medical records for personal injury and wrongful death cases and understand environmental influences on disease (remember the coal workers' black lung cases? And of course there is asbestotis, cancer, and aspergillus now. Not to mention the toxins we deal with where I work that our industrial employees are exposed to. We do health screenings, etc. of industrial workers and study disease clusters, etc., too), and then, of course, I worked for a medical corp. a while ago where I was provided with some medical courses (and certification in one minor thing, i.e. hemodialysis theory) there, too.

I will say, whether it's good or bad, that I sure have learned a lot in the past year. Funny thing is, I always wanted to get into the medical field, and not the legal one, but at my age now, and the fact that I have no "degrees" in anything (jack of all trades, master of none), it's looking like I missed my calling.

And like someone said somewhere, maybe not here; that for some reason, the NMSS (even though they keep in contact with me and are encouraging), when I flat out volunteer, seem to balk at allowing me to help in some way.

Well, now that I've spilled my guts about things you guys could care less about....LOL............to get back to this post, that's also why I've been posting articles and such, hoping that that will help anyone who IS trying to keep up with what we're talking about here. It's pretty interesting stuff.

Wesley, where have you been all my life? ROFL Try talking this stuff with your casual friends and co-workers!! HAH! That's why I love this site!

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby OddDuck » Fri Oct 15, 2004 4:32 am

Now, the thing with polyamines is that I see what Wesley originally stated. (It's the same with PTX3.) Those two avenues have been largely left unexplored in MS, and from what I can see, may play pivotal roles.

I can see both sides of that fence, though. I mean, how can you scatter your research forces so far apart and yet be able to keep track of it? Look at how sprawled MS research is now! I have a feeling enough HAS already been ascertained about MS to indicate that there could be/are several different causes (again not unlike causes of cancer) that some researchers have decided to move on to the therapy side of MS instead. Not that we don't need both in MS research, we certainly do. What the front end finds out, the back end can find treatments for.

But one cause, one drug fits all? Nope. Personally, I just don't see it.

Ok...........enough of my "ponderings". LOL Back to science! Can't wait for your next installment, Wesley! In the meantime, I'm about to get myself educated on chromatin. :wink:

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby OddDuck » Fri Oct 15, 2004 5:06 am

Good heavens, here's another of my "oh, yea" comments:

Wesley, your mention of the thymus and birth was interesting. That's sort of what I've questioned a lot, also. That just makes the whole picture that much larger and more complex, though. And as far as the thymus being atrophied that quickly after birth? I'm not certain I agree with that, Wesley. I quote from somewhere, "Thymus continues to grow until the time of puberty and then begins to atrophy." Unless it DOES atrophy TOO quickly. What would happen then? I think you're on the right track there.

Anyway, I agree about the birth issue. I believe the adaptive immune system (the humoral - THAT'S where I knew that term from - and cell-mediated immune responses) must be somehow malfunctioning right from the get-go. B cells (and receptors) are a common denominator between the X chromosome and the adaptive immune system. (The adaptive immune system is the one that can memorize and "recognizes" antigens and self.)

While the adaptive immune system is taking its sweet old time figuring out whether and/or how to react or not, the innate immune system (the dummie of the two) just launches an attack. It only recognizes molecular "patterns". So now suddenly you've got cytokines, NK cells, complement, etc. all going crazy.

BUT.....the thymus is associated with the T cells, not the B cells. The B cells mature in the bone marrow. The T cells mature in the thymus.

Ok......involvement of the thymus and birth would make sense as far as early dysfunction and predisposition to MS, but how would you correlate the thymus with the X chromosome?

To connect immune system dysfunction in MS to the X chromosome would require concentration on the B cell side of the equation, wouldn't it? Thereby (for this exercise) take the thymus right out of it. Correct?

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

PreviousNext

Return to General Discussion

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users


Contact us | Terms of Service