Thanks for posting that. I am feeling more confident about my polyamine hypothesis over the past few years. I presented it at a Sjogren's syndrome meeting in Brest, France in 2009 and, based on that, I was invited to present it in Zurich this past October at an international rheumatoid arthritis conference. What I presented was:
1) EBV invades cells and induces increased c-MYC activity among other things in an attempt to take over control of the cell's machinery.
2) C-MYC induces increased ornithine decarboxylase (ODC) activity which produces putrescine. ODC is one of the key enzymes in polyamine synthesis and putrescine is a precursor of spermidine and spermine, the main polyamines.
3) Putrescine binds an allosteric site on S-adenosylmethionine decarboxylase (SAMDC) to induce increased activity of SAMDC in converting S-adenosylmethionine (SAM) to decarboxylated SAM (dcSAM). dcSAM is used in polyamine synthesis also. SAM is the cell's methyl donor for DNA methylation and so, a decrease in SAM means some genes may lose their epigenetic silencing. In particular, I think the inactive X chromosome could become reactivated in a cell or as the cell divides to two daughter cells. It doesn't have to be damage to the inactive X (as I said 6 years ago) but simply not enough SAM to keep the inactive X inactivated.
4) At Xp22.1 are the polyamine enzymes, spermine synthase (SMS) and spermidine/spermine-N1-acetyltransferase (SSAT1). Normally these are inactive on the inactive X but now they might become reactivated and over-expressed due to loss of DNA methylation of their promoters.
5) Over-expression of SMS and SSAT1 leads to redundant cycling through polyamine synthesis and salvage, using up more SAM. The interesting thing is that, although this produces more spermine and recycled to spermidine, SSAT1 works 3x more rapidly on spermidine than spermine and so the amount of spermidine would drop as spermine and putrescine rise, further exasperating the problem of SAMDC stimulation and SAM decrease. In fact, the route of putrescine production from spermidine by SSAT1 may become more significant than the putrescine production under some pathological conditions, such as I am describing. Also, I suggest that the change in putrescine/spermidine/spermine could affect the micro-environment, i.e. neighboring cells besides the cell initially affected by the EBV infection.
6) So, with the possible drop in spermidine while spermine and putrescine increase, it could affect myelin formation in the micro-environment.
The presentation went fairly well. Of course I had a lot of pictures to explain the ideas. I can explain things a lot further than this, such as the creation of auto-antigens like citrullinated proteins, but I am in the process of writing up an article explaining it. Once I get it published I can talk about it more. The problem is that there are limits on the size of articles and that keeps me from explaining ideas sufficiently to get them across with all the details and discussing the supporting references.
Anyway, below are some more articles that I have seen in the past regarding spermidine and myelin. There are other articles on treatment of autoimmune diseases (such as lupus models) in mouse models with such things as difluoromethylornithine, an analog of ornithine that can inhibit ODC.
THE REGIONAL DISTRIBUTION OF THE POLYAMINES SPERMIDINE AND SPERMINE IN BRAIN
G. G. Shaw, A. J. PatemanArticle first published online: 4 OCT 2006
Journal of Neurochemistry
Volume 20, Issue 4, pages 1225–1230, April 1973
Shaw, G. G. and Pateman, A. J. (1973), THE REGIONAL DISTRIBUTION OF THE POLYAMINES SPERMIDINE AND SPERMINE IN BRAIN. Journal of Neurochemistry, 20: 1225–1230. doi: 10.1111/j.1471-4159.1973.tb00091.x
The distribution in brain of the polyamines spermidine and spermine is described in the rat, dog, sheep, rabbit and in man. The distribution pattern was about the same in all the species, spermidine concentration being highest in areas rich in white matter. The concentration of spermine was lower than that of spermidine and showed less variation from area to area. Rat brain polyamine content was the same in rats killed by decapitation as in those killed by rapid freezing in liquid nitrogen and was also unchanged up to 48 h after the death of the animal.
Volume 10, Issue 3, December 1978, Pages 335-340
Spermidine: A constituent of the myelin sheath?
Spermidine, an aliphatic polyamine present in high concentrations in the white matter, could act as a bivalent ligand stabilizing myelin lamellae. To seek an answer to the title's question, polyamines were extracted from the subcellular fractions of rat brain after intracerebral injection of [14C]putrescine, a precursor of spermidine. Purified myelin contained a considerable amount of spermidine but only traces of spermine. All other fractions contained both polyamines in various proportions. The specific activity of myelin spermidine was much lower than that of any other fraction. Results support the idea of an intrinsic localization of spermidine in myelin, rather than contamination.
Journal of Neurobiology
Volume 6, Issue 3, pages 267–275, May 1975
Alterations in the accumulation patterns of polyamines in brains of myelin-deficient mice
Diane H. Russell, Hans Meier
Quaking mutants and jimpy mutants of mice have known deficiencies of myelination of the central nervous system, as well as lesser involvement of the peripheral nervous system. Both mutants also have altered polyamine synthesis and accumulation, particularly in the hindbrain and spinal column. The ratio of spermidine/spermine, which generally is higher in tissues with high rates of biosynthetic activity, was significantly lower in the mutants as compared to their normal siblings. In quaking mutants, 5 months of age, the spermidine concentration of hindbrain and spinal column was 60% that of controls. In contrast, the decreased spermidine/spermine ratio in jimpy mutants resulted from a marked increase in the spermine concentration in both forebrain and hindbrain. Alterations in the spermidine/spermine ratio could lead to reductions in the biosynthetic potential of the brain during development.