I'll take a stab on the relapsing-remitting aspect. I've read up on some other diseases that also have relapsing:remitting aspects to them, some with serious neurological consequences. These diseases have a known cause; they are caused by inborn errors of metabolism. Some of them are mitochondrial abnormalities.
Key triggers appear to be stress, as Chris55 has pointed out. The stress can be infectious, exhaustion caused by over-exertion, lactation following pregnancy, psychological, etc. The stress can be anything that alters metabolism, such as a fever. I've read a lot about different diseases in infants where the baby was born apparently normal, but once it got sick with some sort of infection and fever, a whole cascade of symptoms related to the metabolic problem showed up. An example of this is biotinidase deficiency, another is Hartnup, which involves nicotinamide. Hartnup disorder can result in periodic CNS effects. Both biotinidase deficiency and Hartnup are treatable with vitamin supplements. Here is an e-medicine description of biotinidase deficiency if interested in technical details:
Babies born with severe biotinidase deficiency have serious problems due to demyelination and other things immediately, but those with partial deficiency may only have clinical problems under conditions of metabolic stress. Biotinidase deficiency caught my eye because biotin levels were found to be lower the in serum and CSF of MS patients than controls (Anagnostouli et al., 1999). If, for example, MS patients are short biotin, they may have reduced repair of damaged myelin. I'm surprised there hasn't been more followup on this finding. Hartnup disorder caught my eye because I had ataxia and facial lupus-like rash around the time of my diagnosis. This makes me think that at least some cases of MS (and I personally think MS is a multitude of different diseases) might be due to the presence of some metabolic error, or combination of errors, and/or some other factor that isn't severe enough to show up at birth or early childhood but is more subtle, and the damage gradually accumulates and starts showing up in adults. Some of these defects are treatable with changes in diet and/or supplements, and some are not. The two I brought up here are fortunately treatable, there are hundreds, if not thousands of other abnormalities. Although the full blown diseases are usually rare, carrying one bad gene or a gene for a partial deficiency is not all that rare. It is possible that MSers have reduced activity for metabolic enzymes.
So my theory is that at least some MSers probably have a yet-unidentified metabolism problem, and by metabolism I mean biochemical conversion of substrates into cellular energy. There is recently interest in looking at mutations and genetic polymorphisms in the mitochondrial DNA of MS patients. Kalman, 2006 has a recent review. Kumleh et al. 2006 is an interesting paper on a mitochondrial study in Iranian MS patients. This is the area of research that has the greatest hope in finding a cause, in my opinion. And I believe we won't get decent treatments until causes are found - I suspect there is more than one "MS disease", and therefore more than one cause.
I was thinking that if there is am underlying metabolic error, and due to the error the nerve cells are more prone to damage and death, especially under periods of high stress, then the immune system might move in and attempt to clean up the damage and maybe do some more damage on its own, and this is a "relapse". The underlying metabolic error persists of course, and process continues, aggravated under periods of stress. The immune system itself might not be abnormal, it might, at least early on, be trying to respond to something abnormal going on in the nerve cells. Nerve cells require a lot of oxygen and energy, that is why the brain is the most sensitive organ to go out during lack of oxygen and the organ most likely to take permanent damage if it happens. What got me thinking about this is cyanide and the following old abstract. Cyanide is a specific poison of mitochondrial respiration, that is, it keeps the mitochondria from being able to use oxygen. Defective mitochrondrial enzymes may have the same effect. Does cyanide cause demyelination? Yes indeed. Cyanide was used experimentally to cause demyelination in animals, but unfortunately most of those articles don't have abstracts available on PubMed. Here is one oldie that talks about it and the following immune response involving macrophages. This cyanide example may have nothing to do with MS, but shows an example that interference with mitochondrial respiration can cause demyelination and a subsequent immune response. I wish this work would be repeated with modern techniques evaluating immunological response, since immunology has changed so much since 1975. This paper shows that changes to myelin, in response to cyanide, came before the immune response. Something similar MIGHT happen in the presence of an inherited mitochondrial enzyme defect and look like MS, that is my speculation.
: Exp Pathol (Jena). 1975;11(5-6):233-8. Links
Fatty acid pattern of cerebral lipids in cyanide encephalopathy.
From the analysis of the fatty acid spectrum of the individual lipid fractions of the cerebral white matter in cyanide induced encephalopathy would appear that essentially the phosphatidyl ethanolamine and plasmalogen fractions showed appreciable deviations from the control spectra. The observed changes in the cholesteryl ester composition did not correlate with the macrophage reaction, which is known to appear as late as 14 days after HCN intoxication when morphological signs of demyelination become apparent. Neither was there a correlation between the alterations of the phosphatide fatty acid composition and that of cholesteryl esters. It thus would appear that esterification of cholesterol in the myelin of rats occurring during early stages following cyanide intoxication constitutes one of the primary factors injuring the myelin sheath. The same conclusion seems to be applicable to the changes in fatty acid composition of the white matter phospholipids.
PMID: 1233309 [PubMed - indexed for MEDLINE]
Alternatively, the immune system might get suppressed or otherwise deranged in the presence of an enzyme deficiency. and result in infections tht would not otherwise occur - as an example people deficient in biotinidase with severe and persistent fungal infections. If the infection was in the CNS this up and down might look like MS. This is a little like what you were suggesting. I'm not convinced that the immune system is the root problem in MS, though, or the root problem in all cases. Just ideas.
If it's not autoimmune, then treatments such as Tovaxin, which is designed to reduce the numbers of autoreactive t-cells, should not help.Lyon wrote:I use the term "autoimmune" because that's the term people are familiar with. In reality I'm not sure that MS is autoimmune and I'm not sure it matters to me whether or not it's autoimmune.
Most people who believe its not autoimmune, think that the immune system comes in and causes further damaage, after the initial process has happened. By stopping this second stage (ie the secondary autoimmune action), maybe the initial damage is not so great, and easily repairable by the body. Thus, Tovaxin would appear to work. Just a thought.NHE wrote:If it's not autoimmune, then treatments such as Tovaxin, which is designed to reduce the numbers of autoreactive t-cells, should not help.
Here you go. The problem is a protein causing relapes.
http://www.msrc.co.uk/index.cfm?fuseact ... N=50664116
Molecule linked to autoimmune disease relapses identified 03 December 2006
The ebb and flow of such autoimmune diseases as multiple sclerosis, lupus and rheumatoid arthritis has long been a perplexing mystery. But new findings from the Stanford University School of Medicine bring scientists closer to solving the puzzle, identifying a molecule that appears to play a central role in relapses.
The study, to be published in the Dec. 3 advance online edition of Nature Immunology, lays the groundwork for a way to determine when a relapse is about to occur, and could eventually lead to a treatment to prevent relapses. “Right now, there is no good blood test to evaluate when a person is going to have a flare-up,” said senior author Larry Steinman, MD, professor of neurology and neurological sciences. “If we had one, we might be able to give them prophylactic preventive medication.”
The current study had its genesis five years ago: In a paper published in 2001 in the journal Science, Steinman found that a protein called osteopontin was abundant in multiple sclerosis-affected brain tissue, but not in normal tissue. Since then, other groups have confirmed that osteopontin is elevated just prior to and during a relapse of the disease in M.S. patients.
Although the protein had been known to play a role in bone growth, it was unclear why it would be associated with multiple sclerosis, which results when the immune system attacks the protective myelin sheath surrounding nerve cells.
To explore this question, Eun Mi Hur, PhD, who was then a graduate student in Steinman’s lab, began using a mouse model of multiple sclerosis (experimental autoimmune encephalomyletis, or EAE) to investigate how osteopontin could cause these flare-ups. She and Steinman gave osteopontin to mice that had already experienced paralysis, similar to that of an M.S. patient, and found that the mice then experienced a relapse of the disease.
The researchers also found that the relapse would occur sometimes in an area of the brain other than the site of the original attack. For example, after receiving the osteopontin, some animals that had previously suffered paralysis became blind from a condition called optic neuritis. One feature of multiple sclerosis is that the flare-ups can affect different parts of the nervous system at different times.
“When I saw that all mice with EAE relapsed and died from the disease after about a month of osteopontin administration, I was surprised,” said Hur, the study’s first author who is now a postdoctoral scholar at Caltech. “I got a strong belief that a high level of osteopontin in patients’ blood and tissue is a major contributor of the relapse and progression of the disease.”
Through the mouse studies and molecular characterisations, Hur and Steinman showed that osteopontin - produced by immune cells and brain cells themselves - promotes the survival of the T cells that carry out the damaging attack on myelin; by increasing the number of these T cells, osteopontin increases their destructive potential. These results could be applicable to many other autoimmune diseases, including rheumatoid arthritis, type-1 diabetes and lupus.
Indeed, the effect of osteopontin may severely alter the way the immune system works. Normally, after the immune system does its job - eradicating a microbe, for instance - the response is then dialed down. If this didn’t happen, the immune response would go on indefinitely. Imagine a cold or an attack of poison oak that would last forever.
One of the ways that the immune response is muffled is that the activated T cells die in a process known as apoptosis. That is precisely what osteopontin seems to prevent. Osteopontin lets the T cells linger in the blood, ready to attack again. “We don’t know exactly what triggers that new attack but the cells certainly are around and ready to do it,” said Steinman. So scientists now face the challenge of figuring out how and why osteopontin is produced. “We’re back to the chicken-and-the-egg problem,” said Steinman. “We know the egg, so why did the chicken lay it” That is a trickier problem to work out.”
Even without knowing the answer to that question, there is one inviting practical use of their observations: Osteopontin could be used as a marker of an impending relapse. What’s more, if the protein could be blocked, it might thwart the relapse from ever occurring. Steinman’s lab is working to develop antibodies to inactivate the protein’s effect. “It’s still a long road between saying we want to do it and getting the antibodies, getting it approved by the FDA and getting it tested,” said Steinman, “but we are determined to do that.”
Still, Steinman offered a caveat. Researchers may find that blocking osteopontin has undesirable side effects. The protein may serve other purposes in addition to promoting survival of immune cells. It could also be vital to the body’s ability to produce myelin, a function that could cause severe problems if disrupted. “Like a lot of important biological molecules, osteopontin has a Janus-like quality - a bad side and a good side,” Steinman said. “We’re going to be extremely lucky if we give the antibody opposing osteopontin and derive just the good side: We stop the autoimmune attack but don’t interfere with the survival of other cells.”
Further study will determine whether thwarting osteopontin’s effect yields new types of treatments for autoimmune diseases, but regardless, it is likely to lead to discoveries in a host of areas. “I think osteopontin will turn out to be important in a lot of processes, spanning autoimmunity to stem cells,” said Steinman. “It’s probably going to turn out to be a very basic growth factor.”
Source: Stanford University Medical Center
I apologize if I came across that way. It wasn't my intent. My definition of autoimmune is fairly simple and, in a nutshell, it means that the some part of the immune system, e.g., B-cells, T-cells, etc., is targeting self antigens, e.g., myelin, vs. non-self antigens, e.g., bacteria of viruses. I've read, and posted links in the past, that nearly everyone has some autoreactive T-cells. However, in most people these cells are weeded out by the immune system which is pretty good at regulating itself. However, in folks with autoimmune disease, these cells are not controlled to the same extent and are allowed to proliferate and do their dirty work such as damaging self tissues.Lyon wrote:Hi NHE,NHE wrote:If it's not autoimmune, then treatments such as Tovaxin, which is designed to reduce the numbers of autoreactive t-cells, should not help.
OK smartypants I lean towards autoimmune but I can't prove it and there are people around here who want to argue that one into the ground.
My remarks regarding Tovaxin can be explained by noting that the principle basis of the treatment is to collect "myelin reactive T-cells" and then train the immune system to eliminate them via vaccination of these cells once they're rendered incompetent (no cell division). Now whether or not Tovaxin works has yet to be fully determined. It appears to have worked reasonably well in a phase IB/IIA study with 15 people. The current phase IIB study is stated to include 150 people. The results of which should give us a better idea of whether or not the treatment will work in the general population of MS patients. If so, then they'll do at least one phase III study to obtain FDA approval (the reason that I say "at least one phase III" is that we have a family friend that regularly invests in biotech stocks who was at recent seminar for traders where it was discussed that Opexa may be required to perform 2 phase III studies since their treatment is such a novel approach). However, going back to those myelin reactive T-cells. If these autoreactive T-cells did not exist, i.e., if there were no T-cells targetting self antigens, then the basis for the treatment would be a sham. The fact that the myelin reactive T-cells do exist confirms, at least under my definition, that MS is, at least in some part, autoimmune.
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