New Stanford research: stroke and the immune system

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

New Stanford research: stroke and the immune system

Postby cheerleader » Mon Jul 25, 2011 3:33 pm

New research from Stanford:


Scientists discover potential stroke treatment that may extend time to prevent brain damage

STANFORD, Calif. — A naturally occurring substance shrank the size of stroke-induced lesions in the brains of experimental mice — even when administered as much as 12 hours after the event, Stanford University School of Medicine researchers have shown. The substance, alpha-B-crystallin, acts as a brake on the immune system, lowering levels of inflammatory molecules whose actions are responsible for substantial brain damage above and beyond that caused by the initial oxygen deprivation of a stroke.

The only currently approved drug for stroke — tissue plasminogen activator, or tPA — dissolves clots that keep oxygenated blood from reaching brain tissue. To be effective, tPA must be administered within about 4.5 hours after the stroke. But patients' brains must first be scanned to rule out the possibility that the stroke was caused by bleeding, which tPA would exacerbate, rather than by blockage.

Moreover, tPA does nothing to counter the stroke's insidious inflammatory aftershock: a flood of noxious chemicals secreted by angry immune cells that rush in to the affected area, causing significant further damage.

"The brain doesn't roll over and play dead when it's under attack," said Lawrence Steinman, MD,
the other senior author of the new study, who is the George A. Zimmermann Professor of Neurology and Neurological Sciences and Pediatrics as well as chair of Stanford's interdepartmental program in immunology.

In an earlier study, published in Nature in 2007, Steinman and his colleagues found that the presence of alpha-B-crystallin could help reduce the severity of brain damage caused by multiple sclerosis, a chronic, debilitating autoimmune disease of the brain. Other studies published this year by his group have shown that alpha-B-crystallin limits the damage caused by blood-supply cutoffs to heart tissue and the retina.

It seemed logical to see if this protein could mitigate the effects of a stroke. "We made a jump from its relevance in inflammatory diseases such as multiple sclerosis," Steinberg said. "To my knowledge, nobody had looked at concentrations of alpha-B-crystallin after a stroke, either in people or in an experimental animal model before."

http://www.eurekalert.org/pub_releases/ ... 072111.php

was this such a large leap, really?
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
User avatar
cheerleader
Family Elder
 
Posts: 5015
Joined: Mon Sep 10, 2007 3:00 pm
Location: southern California

Advertisement

Postby 1eye » Mon Jul 25, 2011 5:14 pm

Any leap that is based on a connection we know exists, and works to help us, will discourage willful denial, and encourage others to make similar leaps. Any side bets on the effects on EAE mice? Stenotic/ligated animals?

I think it is great that safety work can be done for both diseases, though the dosage for stroke vs 'MS' is likely very different.
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience
User avatar
1eye
Family Elder
 
Posts: 2875
Joined: Wed Mar 17, 2010 4:00 pm
Location: Kanata, Ontario, Canada

Postby zinamaria » Mon Jul 25, 2011 9:14 pm

User avatar
zinamaria
Family Elder
 
Posts: 296
Joined: Fri Dec 04, 2009 4:00 pm

Postby cheerleader » Tue Jul 26, 2011 7:09 am

Just picked up in the British press--
link

An immune reaction occurs in the brain after O2 deprivation....
A naturally occurring substance which slows the immune system could be used to reduce the swelling after stroke which adds to the initial damage caused to the brain by oxygen deprivation.

A study on mice showed that a protein known as alpha-B-crystallin, which is naturally produced in response to stress, can work like a sponge to soak up inflammatory molecules in the brain and reduce further damage.
Stroke, the third most common cause of death in Britain, happens when blood flow to the brain suddenly drops due to a clot or bleeding.
Mice which were genetically engineered to lack alpha-B-crystallin suffered more brain damage from stroke than normal mice in an experiment by Stanford University scientists.

cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
User avatar
cheerleader
Family Elder
 
Posts: 5015
Joined: Mon Sep 10, 2007 3:00 pm
Location: southern California

Postby Ernst » Tue Jul 26, 2011 8:10 am

Found this one: "High prevalence of anti-alpha-crystallin antibodies in multiple sclerosis: correlation with severity and activity of disease"

RESULTS:
Sixty-three percent of MS patients exhibited immunoreactivity to alpha-crystallin and this was present in all 4 of 4 non-ambulatory patients with MS. In contrast, serum concentrations in MS patients of antibodies to the small Hsp, Hsp27, and to myelin basic protein were negligible (P<0.001). Serum anti-alpha-crystallin immune responses were detected in significantly lower percentages of patients with other inflammatory neurological diseases (32%, P<0.025), and with non-inflammatory neurological diseases (12%, P<0.001). None of the healthy control individuals showed anti-alpha-crystallin reactivity. The concentration of anti-alpha-crystallin antibodies in patients with MS correlated with severe disease (P<0.05) and with active disease (P<0.025).

CONCLUSION:
Our observations support the notion that anti-alpha-crystallin autoimmune responses may contribute to pathogenicity in MS and may represent a mechanism of how recurrent attacks of MS develop subsequent to an isolated demyelinating episode.

http://www.ncbi.nlm.nih.gov/pubmed/10478576

And this means that....?
My wife's 3 yrs post video: http://www.youtube.com/watch?v=eLeqLps8XR8

Our family: http://www.youtube.com/watch?v=p_QCKxeQAlg
User avatar
Ernst
Family Elder
 
Posts: 294
Joined: Sat Nov 15, 2008 4:00 pm
Location: Rovaniemi

Postby cheerleader » Tue Jul 26, 2011 9:03 am

Hi Ernst-
great find. That's older research on alphaB crystalline. What the paper means is that the worse the immune attack on alphaB-crystalline, the worse the MS. Alpha B crystalline is sent in by the body to help heal after an injury, but the immune system attacks it....

Like a runaway truck careening down a mountain and then having the brakes fall off, the immune attack against alphaB-crystallin worsens the situation," says Lawrence Steinman, M.D., professor of neurology and neurological sciences. And remarkably, he notes, addition of that protein works like restoring the failing brakes, returning control.


What is interesting to note is that Steinman and his Stanford team are finding the same immune system reaction against alphaB-crystallin in stroke....not just MS.
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
User avatar
cheerleader
Family Elder
 
Posts: 5015
Joined: Mon Sep 10, 2007 3:00 pm
Location: southern California

Postby 1eye » Tue Jul 26, 2011 1:19 pm

Bring on the EAE. Bring on the other animal models.
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience
User avatar
1eye
Family Elder
 
Posts: 2875
Joined: Wed Mar 17, 2010 4:00 pm
Location: Kanata, Ontario, Canada

Postby ThisIsMA » Wed Jul 27, 2011 10:45 am

cheerleader wrote:What is interesting to note is that Steinman and his Stanford team are finding the same immune system reaction against alphaB-crystallin in stroke....not just MS.


Strokes are caused by blood clots in the brain which result in hypoxia. Does that hypoxia then cause stroke brain lesions?

PWMS have hypoxia, and also have brain lesions. Does that hypoxia then cause MS brain lesions?

In MS, (and in stroke?) maybe its the hypoxia that causes the release of alphaB-crystallin, and the immune system then attacks the alphaB-crystallin, causing the lesions as described in this excerpt from a previously linked to article on MS in this thread:

http://www.news-medical.net/news/2007/06/18/26522.aspx

The recognition of this protein's role in multiple sclerosis began more than a decade ago, when Dutch researcher Johannes Van Noort, PhD, found that the main stimulant of the immune system's attack on the brain was not the presumed culprit of one of the parts of myelin, but alphaB-crystallin, the major structural protein of the lens of the eye.

"For some reason, the protein gets turned on in the brain where it's not expected to be,"


If the unknown reason that alphaB-crystallin gets turned on in the brain is hypoxia, and if hypoxia in MS is caused by CCSVI, then CCSVI causes MS!?

I feel like I'm not articulating this well...

Did any of that research say that hypoxia causes the release of alphaB-crystallin?
DX 6-09 RRMS
User avatar
ThisIsMA
Family Elder
 
Posts: 151
Joined: Sat Feb 13, 2010 4:00 pm
Location: USA

Postby cheerleader » Wed Jul 27, 2011 10:53 am

Just crossed posts with you, This Is...
Yes, alpha b crystallin comes in to help with hypoxia.
Yes, I do believe CCSVI creates diffuse hypoxia in the brain and endothelial dysfunction of the blood brain barrier, and that this is what MS really is. More research is illucidating how slowed perfusion affects the MS brain, and BOLD MRI technology is showing how lower levels of O2 are found in situations of slowed perfusion. I do believe this connection to alpha b crystallin is part of the puzzle...since it shows up in hypoxia, MS, and stroke.

The reason this new treatment is so appealing is that it isn't suppressing t or b cells (which can lead to PML and other problems)...it is increasing alpha b crystallin.

What is really interesting to note is that it was at first assumed alpha b crystallin was HARMING the brain, since the protein showed up in the MS brains, where it wasn't supposed to. But years later, we learn that it is actually helping the brain, by sopping up inflammation.

Alpha b crystallin is very important for the endothelium, as it regulates expression of VEGF in hypoxic stress.

Hypoxic stress results in increased expression of vascular endothelial growth factor (VEGF), a known stimulator of angiogenesis. Increases in expression result in both properly folded and misfolded VEGF proteins. Misfolded VEGF is exported from the endoplasmic reticulum (ER) into the cytoplasm and ubiquitinated. (A) Hypoxic stress also stimulates phosphorylation of αB-crystallin (αB). Phosphorylated αB-crystallin binds misfolded, monoubiquitinated VEGF and returns it to the ER, where it is folded correctly and transported to the Golgi apparatus for secretion. Thus, the secretion of VEGF is up-regulated, angiogenesis occurs, and hypoxic stress may be reduced. (B) Properly folded VEGF is still transported to the Golgi and secreted. In the absence of αB-crystallin, misfolded, monoubiquitinated VEGF accumulates in the cytoplasm. Some of this will become polyubiquitinated and degrade. The rest of the misfolded VEGF can aggregate, leading to increased stress on the cell. Because misfolded VEGF cannot be transported back to the ER to be refolded, decreased secretion of VEGF occurs and hypoxic stress continues.

http://bloodjournal.hematologylibrary.o ... /3181.full
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
User avatar
cheerleader
Family Elder
 
Posts: 5015
Joined: Mon Sep 10, 2007 3:00 pm
Location: southern California

Postby cheerleader » Wed Jul 27, 2011 11:18 am

Here's the complete Stanford paper, which explains how the original theory of alpha b crystallin as an auto antigen in MS (due to the immune system response to this protein) was found to be incorrect.

The association of a B-crystallin (heat shock protein [Hsp] B5) with multiple sclerosis (MS) has been a puzzling story (1). Van Noort and colleagues (2, 3) first proposed the protein to be an autoantigen in 1995 based on the reactivity of PBMCs from MS patients and healthy control subjects to pro- liferate in response to a fraction of myelin from MS brains containing a B-crystallin

http://robinsonlab.stanford.edu/publica ... uno_11.pdf

Of course, the original researchers, Van Noort et al, have written letters to publications asserting that their original research is correct, Stanford is wrong, and alpha b crystallin is an autoantigen.

But because alpha b crystallin comes in to the brain to help with stroke, ischemia and hypoxia, I can't help but think that the Stanford researchers are correct, and this protein is responding to low O2 and ischemic brain damage and is trying to help...but more research needs to be done.
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
User avatar
cheerleader
Family Elder
 
Posts: 5015
Joined: Mon Sep 10, 2007 3:00 pm
Location: southern California


Return to Chronic Cerebrospinal Venous Insufficiency (CCSVI)

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users