Study: Endothelial-related protien found in MS Lesions only

[ThisIsMA]

Has anyone noticed this article, and does it have any possible significance for CCSVI? I know the study itself is focused on predicting which disease modifying drugs will work in which patients, but I noticed the following paragraph in this article about the study:

http://scopeblog.stanford.edu/2013/09/3 ... -response/

the study authors (including Stanford geneticist Michael Snyder, PhD) identified more than 2,000 proteins that were activated in MS lesions. One of those proteins, sphingosine-1-phosphate receptor 1, was activated only in the MS brain samples, suggesting its importance in MS pathogenesis.

So I looked up the wikipedia article for that protein, and the protien is called: endothelial differentiation gene 1 (EDG1)

Here's a link to the Wikipedia article about that protein:

http://en.wikipedia.org/wiki/S1PR1

Here's an excerpt from the wikipedia page:

Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5).[1] S1PR1 was originally identified as an abundant transcript in endothelial cells[2] and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation.[3][4] In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.[5][6]

There's a lot more to the wikipedia article if you go to the link above.

Mary Ann

[Cece]

The Wikipedia article had a link to this article:

Glia. 2010 Sep;58(12):1465-76. doi: 10.1002/glia.21021.

Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions.

Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD, Van Der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE.


Source

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.


Abstract


Sphingolipids are a class of biologically active lipids that have a role in multiple biological processes including inflammation. Sphingolipids exert their functions by direct signaling or through signaling by their specific receptors. Phosphorylated FTY720 (FTY720P) is a sphingosine 1-phosphate (S1P) analogue that is currently in trial for treatment of multiple sclerosis (MS), which targets all S1P receptors but S1P(2). To date, however, it remains unknown whether FTY720P may exert direct anti-inflammatory effects within the central nervous system (CNS), because data concerning S1P receptor expression and regulation under pathological conditions in the human brain are lacking. To investigate potential regulation of S1P receptors in the human brain during MS, we performed immunohistochemical analysis of S1P receptor 1 and 3 expression in well-characterized MS lesions. A strong increase in S1P receptor 1 and 3 expression on reactive astrocytes was detected in active and chronic inactive MS lesions. In addition, we treated primary cultures of human astrocytes with the proinflammatory cytokine tumor necrosis factor-alpha to identify the regulation of S1P(1/3) on astrocytes under pathological conditions. Importantly, we demonstrate that FTY720P exerts an anti-inflammatory action on human astrocytes by limiting secretion of proinflammatory cytokines. Our data demonstrate that reactive astrocytes in MS lesions and cultured under proinflammatory conditions strongly enhance expression of S1P receptors 1 and 3. Results from this study indicate that astrocytes may act as a yet-unknown target within the CNS for the anti-inflammatory effects observed after FTY720P administration in the treatment of MS.

[cheerleader]

Sphingosine 1 phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier---
http://www.jneuroinflammation.com/content/9/1/133

This paper is studying how FTY720P modulates the endothelium and dampens inflammation by modulating the S1P5 receptor....

Under normal conditions, the brain endothelium promotes immunoquiescence of the brain by a low expression of cell adhesion molecules and undetectable detection of the production of proinflammatory cytokines and chemokines, thereby limiting attraction and subsequent transendothelial migration of leukocytes.

But it's not only in MS--and to claim that S1P1, 3 or 5 is only showing up in MS lesions is simply not true.
We see the same response in ischemia and vascular disorders---

Moreover, in other vascular disorders, such as atherosclerosis, FTY720P exerts protective effects by dampening ongoing inflammatory processes in the vascular smooth muscle cells.

Moreover, in models of brain ischemia FTY720P was able to reduce infarct size and could, in transient focal cerebral ischemia, positively regulate neurological deficits. Observed beneficial effects were associated with a reduction in activated neutrophil and microglia/macrophage cell numbers and, in line with our results, also with reduced numbers of ICAM-1 positive blood vessels [41]

We demonstrate that endogenous endothelial S1P5 represents an essential receptor for optimal BBB function by regulating different aspects of the BBB, including the expression of cell–cell junction proteins and efflux pumps. Importantly, we demonstrate that S1P5 is essential for maintenance of the immune quiescent state of brain ECs and that this is in part mediated by NF-κB. Our data also reveal the therapeutic potential of S1P5 agonism during neuroinflammation as S1P5 specifically limits neurovascular inflammation and transendothelial leukocyte infiltration.

The Stanford research can't say this is an "autoimmune" response. This is a response to ishemia.

Here's a paper where they give FTY720 to rats after occluding their arteries and giving them hypoxic injury. You cut off O2 to the brain, you're going to see S1P1, S1P3 and S1P5 activated in the brains or mice and men. And apparently, FTY720 can be neuronally protective in this situation. But isn't it a better idea to reduce hypoxia, if you can?

http://stroke.ahajournals.org/content/41/2/368.full.pdf
cheer

[Cece]

the study authors (including Stanford geneticist Michael Snyder, PhD) identified more than 2,000 proteins that were activated in MS lesions. One of those proteins, sphingosine-1-phosphate receptor 1, was activated only in the MS brain samples, suggesting its importance in MS pathogenesis.

When they see it was active only in the MS brain samples, were the other brain samples all healthy controls? I found the actual article but it's not that clear.
http://www.nature.com/ni/journal/vaop/n ... .2730.html

[cheerleader]

When they see it was active only in the MS brain samples, were the other brain samples all healthy controls? I found the actual article but it's not that clear.
http://www.nature.com/ni/journal/vaop/n ... .2730.html

Good question, Cece. It isn't clear at all. Interestingly, S1P1 shows up in hypoperfusion/reperfusion injury-and we've both written about MS as a disease of perfusion/reperfusion injury....no one mentions "autoimmune" in any of these studies. They mention ischemia, vascular permeability and endothelial barrier integrity.
http://jasn.asnjournals.org/content/21/6/955.abstract
http://www.ncbi.nlm.nih.gov/pubmed/20338995
http://www.ncbi.nlm.nih.gov/pubmed/20458275
http://www.ncbi.nlm.nih.gov/pubmed/16403835
http://www.nature.com/ki/journal/vaop/n ... 3345a.html

Thanks, Mary Ann, for finding the Stanford story...it's very relevant!

cheer

[1eye]

Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5).[1] S1PR1 was originally identified as an abundant transcript in endothelial cells[2] and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation.[3][4] In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.[5][6]

There's a lot more to the wikipedia article if you go to the link above.

Mary Ann

I think there may be more to this gene and to FTY720 than people realize. It may be responsible for the weird duality/complementarity of "MS" and cancer. My side of my family doesn't get cancer. Maybe FTY720 has an affect on this gene that will help prevent a pre-cancerous cell from acquiring the ability to become immortal. The reason they become cancerous has to do with the maturation of blood vessels. In tumours, there is uncontrolled splitting of vessels into random numbers of new ones. That affects the tumour's growth and size.

FTY720 was, according to somebody, created from a Chinese nostrum supposed to confer long life. The drug is made from the 'nostrum' which is supposed to be made from the discarded skins of cicadas. I guess that's like Spring Cleaning for a Cicada.

There must be a gene controlling the fractal splitting of blood vessels, usually only into 2. That would also control the diameter and length before the splitting happens, how many times it happens, etc. So perhaps FTY720 helps prevent cancer in those genetically disposed.

I was supposed to be on a trial of FTY720 that was one of the early ones, before it became Gilenya. Before the trial could start, my neuros decided I was no longer eligible, as they had decided (wrongly) that I was past EDSS 6, and therefore I was SP"MS". If I wasn't 6.0 then, they made sure I would never avoid it, by denying me that drug. At that time I was walking, driving and playing guitar. And the genius behind it all patronizingly told me not to worry, that for sure I would get it back. Just to be mean, is the only reason I can think of.

That was not the only time I was assaulted and gravely injured, sullying the name of science, by supposed doctors. And of course a person who was willing to be an FTY720 guinea-pig cannot get it even now, because since then he has progressed past EDSS 6 for sure.