I have said before that I believe MS and lupus are related in mechanism, just differ in location (inside vs outside BBB) and the resulting symptoms and consequences. Both seem to have some retrovirus involvement:
1: J Rheumatol. 2001 Mar;28(3):533-8. Links Comment in:
J Rheumatol. 2001 Mar;28(3):461-4.
Quantitative analyses of messenger RNA of human endogenous retrovirus in patients with systemic lupus erythematosus.Ogasawara H, Naito T, Kaneko H, Hishikawa T, Sekigawa I, Hashimoto H, Kaneko Y, Yamamoto N, Maruyama N, Yamamoto N.
Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
OBJECTIVE: Human endogenous retrovirus (HERV) has emerged as a possible causative agent of systemic lupus erythematosus (SLE). To investigate the role of HERV in the etiology of SLE, we performed quantitative analyses of messenger RNA (mRNA) of the HERV clone 4-1 in patients with SLE. METHODS: Reverse transcriptase (RT)-polymerase chain reaction (PCR) and real-time quantitative PCR (RQ-PCR; TaqMan methodology) were used in this experiment. RESULTS: The quantities of mRNA of the HERV clone 4-1 gag region in patients with SLE were significantly higher than in healthy controls, and the amounts of such mRNA in the patients were decreased by steroid treatment. CONCLUSION: These phenomena may be related to the production of viral components derived from HERV clone 4-1 and contribute to the pathogenesis of SLE; studies using a larger number of patients are required to confirm these points.
We should think of the consequences of activation of an endogenous retrovirus, but more specifically, the activity of a reverse transcriptase. It would generate DNA that needs to be methylated, otherwise it would appear to be foreign DNA. I have pointed out before how Alu RNAs located near the ribosomes are much more likely to be reverse transcribed than other RNAs, probably even more so than the retroviral RNAs that have been generated from the retroviral genes. The resulting Alu DNA is very rich in GC content and therefore would require a lot of methylation to suppress its foreign (unmethylated) appearance. Therefore a lot of S-adenosylmethionine (SAM) would be needed for the methylation. But, since the SAM is being used for increased DNA and histone methylation and probably increased polyamine synthesis, there is less SAM available for some of its other functions, such as regulating homocysteine. The homocysteine then increases:
Biochem J. 1994 March 1; 298(Pt 2): 415–419.
Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism.
J W Miller, M R Nadeau, J Smith, D Smith, and J Selhub
Vitamin Bioavailability Laboratory, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111.
In a recent hypothesis [Selhub and Miller (1992) Am. J. Clin. Nutr. 55, 131-138], we proposed that homocysteinaemia arises from an interruption in S-adenosylmethionine's (AdoMet) coordinate regulation of homocysteine metabolism. The present study was undertaken to test a prediction of this hypothesis, that homocysteinaemia due to folate deficiency results from impaired homocysteine remethylation due to the deficiency and impaired synthesis of AdoMet, with the consequent inability of this metabolite to function as an activator of homocysteine catabolism through cystathionine synthesis. Rats were made folate-deficient by feeding them with a folate-free amino-acid-defined diet supplemented with succinylsulphathiazole. After 4 weeks, the deficient rats exhibited a 9.8-fold higher mean plasma homocysteine concentration and a 3.2-fold lower mean hepatic AdoMet concentration compared with folate-replete controls. Subsequent supplementation for 3 weeks of the folate-deficient rats with increasing levels of folate in the diet resulted in graded decreases in plasma homocysteine levels, accompanied by graded increases in hepatic AdoMet levels. Thus plasma homocysteine and hepatic AdoMet concentrations were inversely correlated as folate status was modified. In a second experiment, the elevation of plasma homocysteine in the deficient rats was found to be reversible within 3 days by intraperitoneal injections of ethionine. This effect of ethionine is thought to be exerted through S-adenosylethionine, which is formed in the liver of these rats. Like AdoMet, S-adenosylethionine is an activator of cystathionine beta-synthase and will effectively promote the catabolism of homocysteine through cystathionine synthesis. In crude liver homogenates of the rats treated with ethionine, cystathionine beta-synthase activity was 3-fold higher than that measured in homogenates from vehicle-treated controls.
Do we see anything about homocysteine levels in MS? Yes we do:
J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):189-92
Plasma homocysteine levels in multiple sclerosis.
Ramsaransing GS, Fokkema MR, Teelken A, Arutjunyan AV, Koch M, De Keyser J
Department of Neurology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands.
BACKGROUND: There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS). OBJECTIVE: To investigate if and why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course. METHODS: We compared plasma levels of homocysteine in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress). RESULTS: Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) micromol/l) than in controls (10.1 (2.5) micromol/l; p<0.0001). However, there were no significant differences in homocysteine levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels. CONCLUSIONS: Elevated plasma homocysteine occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.
PMID: 16421120 [PubMed - indexed for MEDLINE]
So the points (my opinions) I am trying to make are:
1. MS and lupus are similar in the initial cellular mechanisms but differ in the symptoms and consequences that appear due to location in the body where it originates, particularly in regards to accessibility by the immune system response. In MS it is more difficult for the immune system to encounter the autoantigens because of the BBB but in lupus the autoantigen/autoantibody complexes freely circulate and windup causing problems elsewhere, like in the kidneys.
2. SAM and its use are important and somehow different in MS (and lupus) from normal subjects, particularly with regards to DNA, histone methylation and polyamine synthesis.
By the way, I continually bring up polyamines as being involved, particularly spermine synthase, since they require SAM for their synthesis:
Ann Neurol. 2006 Sep;60(3):323-34.
Methylthioadenosine reverses brain autoimmune disease.
Moreno B, Hevia H, Santamaria M, Sepulcre J, Munoz J, Garcia-Trevijano ER, Berasain C, Corrales FJ, Avila MA, Villoslada P.
Neuroscience and Gene Therapy Division, Center for Applied Medical Research, University of Navarra, Navarra, Spain.
OBJECTIVE: To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis. METHODS: We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot. RESULTS: We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10). INTERPRETATION: MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases.
regarding MTA and spermine synthase:
FEBS Lett. 1979 Mar 15;99(2):343-5
Methylthioadenosine, a potent inhibitor of spermine synthase from bovine brain
Pajula RL, Raina A.
PMID: 428559 [PubMed - indexed for MEDLINE]
Much effort has recently been made to develop specific inhibitors of polyamine synthesis which may help in elucidating the role of polyamines in cellular metabolism and in cell proliferation in particular [ 11. Furthermore, inhibitors of polyamine synthesis may
find applications as antiproliferative agents. Four enzymes are involved in the synthesis of polyamines in eukaryotic cells, i.e., ornithme decarboxylase, S-adenosylmethionine decarboxylase, and two propylamine transferases, one catalyzing the synthesis of
spermidine, the other producing spermine . Most of the inhibitors presently available are inhibitors of the two decarboxylases, whereas little is known about inhibitors
acting at the propylamine transferase step [ 11. We have recently described an efficient method for the purification of spermine synthase from mammalian tissues using spermine-Sepharose affinity chromatography 231. This enzyme has now been
purified to an apparent homogeneity. The details of the purification procedure and the properties of the pure enzyme will be described elsewhere. In this report we demonstrate that the purified spermine synthase from bovine brain is strongly inhibited by
methylthioadenosine, one of the products of the propylamine transferase reaction. This observation may be important for understanding the regulation of polyamine synthesis as well as for the development of new inhibitors of polyamine synthesis in eukaryotic
And, as I have pointed out before, spermine synthase is on the X chromosomes and is usually only active from the active X, suppressed from the inactive X (think of the female predominance in MS and lupus). Disruption of chromatin due to some stressful event in a few cells like a viral infection, leads to loss of suppression of endogenous retroviral genes and loss of control of other genes, such as spermine synthase. This then taxes the cell’s supplies of SAM for methylation and other key molecules. It really gets complicated explaining this but hopefully you can follow it.