This Is MS Multiple Sclerosis Knowledge & Support Community

The American Academy of Neurology will be meeting in Philadelphia from April 26-May 3. In advance of this meeting, some press releases are being sent out. Apparently, the BIG NEWS in MS research is KIR4.1 antibodies are present in about half of the plasma samples from patients with a pre-clinical diagnosis of MS patients, and this could be a diagnostic and treatment target. According to research by the Technical University in Munich-

The researchers found that KIR4.1 antibody titers were significantly higher for pre-clinical MS patients than healthy controls (P = 0.0185). Seven of the pre-clinical patients were considered KIR4.1 antibody positive, while two had borderline activity and seven were found to be negative. All healthy controls were also KIR4.1 antibody negative. In the longitudinal analysis, pre-clinical MS patients had KIR4.1 antibodies several years prior to the first clinical attack. In individual pre-clinical MS patients, antibody titers varied at different time points. There was no significant difference in titers before and after disease onset
http://www.doctorslounge.com/index.php/news/pb/44720


But research into KIR4.1 antibodies is not new....nor is it exclusive to MS.
We see the same immune reaction to KIR4.1 in hydrocephalus and cerebral edema.
more info--
http://ccsviinms.blogspot.com/2014/02/k ... cture.html

cheer

If KIR4.1 has to do with water transport, then its presence might be due to the abnormal cerebrospinal fluid hemodynamics, and it could also be a pre- and post-angioplasty biomarker for CCSVI patients.

The presence of KIR4.1 is interesting but there is more than one way to interpret it.

I really like the new blog, by the way. It is good to have all the information (and there is so much information!) in one easily linked place.

Cece wrote:If KIR4.1 has to do with water transport, then its presence might be due to the abnormal cerebrospinal fluid hemodynamics, and it could also be a pre- and post-angioplasty biomarker for CCSVI patients.

The presence of KIR4.1 is interesting but there is more than one way to interpret it.

I really like the new blog, by the way. It is good to have all the information (and there is so much information!) in one easily linked place.

Agree, Cece--this discvoery can be interpreted in many ways--but to jump to the conclusion that this is an autoimmune reaction to a water transport protein and discuss developing pharmaceutical treatments BEFORE understanding the mechanism behind this antibody response seems crazy-- this is what keeps getting us in to trouble with new MS medications. Just hoping to outline some connections and get the info out there. The blog is easier to access than Facebook, doesn't have the same stigma. I transferred all my writing from FB, and update on the blog now. Glad it's useful! It's searchable, too.
cheer

cheerleader wrote:Agree, Cece--this discvoery can be interpreted in many ways--but to jump to the conclusion that this is an autoimmune reaction to a water transport protein and discuss developing pharmaceutical treatments BEFORE understanding the mechanism behind this antibody response seems crazy-- this is what keeps getting us in to trouble with new MS medications.

Yes, this is what I was thinking too, that the autoimmune hypothesis supporters are going to lock down on interpreting this in a very limited way.

It's possible that pharmaceutical treatments could be developed that work even in the absence of understanding why it works! It might work because of a vascular reason rather than an autoimmune reason, but it might work, and that's always exciting.

I just got back from the gym & I am feeling very optimistic.

I have just edited this post to write some thoughts about the Kir4.1 situation and the Lucchinetti patterns. The four patterns were reported during the years 1996-2003 in several articles, and then forgotten. We have already a thread about them, from 2009, here:

http://www.thisisms.com/forum/general-d ... c6851.html

At that time, it was already clear that something wrong was in the blood serum of pattern II people. They would respond to plasmapheresis while others didn't.

The reported percentajes of each pattern were around 20% for pattern I, 53% for pattern II (very close to the reported 47% of kir4.1 cases), 25% for pattern III, and a poor 2% for pattern IV. They can still be consulted here:

http://www.mult-sclerosis.org/news/May2 ... Brain.html

The other most statistically significant pattern is pattern III. Reading back the post of 2009 something interesting appears. Is a pattern associated with hypoxia, and looks like white matter stroke

For this reason, I consider natural to associate this pattern III with CCSVI, leaving the pattern II to account for the cases that do not respond to CCSVI. OF course, this implies that MS is two complete different things, at least.

Any thoughts?

New article about Kir4.1 in MS. They confirm the presence of Kir4.1 and they report that they were able to track back the status of the patient's blood serum. It seems they did it by following some CIS patients. Therefore their statement about "6 years before MS" should be read "6 years before clinical MS"

http://www.medscape.com/viewarticle/821075

Yeah--that's also in the story I posted at the beginning of this thread, Frodo.

In the longitudinal analysis, pre-clinical MS patients had KIR4.1 antibodies several years prior to the first clinical attack.

It's taken from a press release from the upcoming American Academy of Neurology conference in Philadelphia in April. There were lots of different write ups about it. I just linked to the one that was open access.
Here are some more:
http://www.eurekalert.org/pub_releases/ ... 021214.php
http://www.medicalnewstoday.com/articles/273121.php


As far as the Lucchinetti/Lesion Project research---Marc (Wheelchair Kamikazee) summed up what many on this board felt back in 2009 when I started a discussion on the Lesion Project--- http://www.thisisms.com/forum/general-d ... c6851.html

I've discussed the findings of The Lesion Project with a number of neurologists, and most of them are a bit skeptical of the findings. They say that even if a patient displays only one type of lesion postmortem, that does not mean that their lesions didn't evolve through different stages over time.

The different patterns could well just be due to the age of the lesion. And there's been no new research on the different "lesion patterns" since then. Lucchinetti has moved on to look at loss of gray matter in MS.

I'm hoping researchers look at the other situations where these KIR4.1 antibodies show up---in cerebral edema and hydrocephalus. There may be more clues in that line of research. http://ccsviinms.blogspot.com/2014/02/k ... cture.html
cheer

cheerleader wrote: The different patterns could well just be due to the age of the lesion. And there's been no new research on the different "lesion patterns" since then. Lucchinetti has moved on to look at loss of gray matter in MS.

Yes. That could be. But the plasmapheresis heterogeneous response was real, and it was confirmed by independent groups. And that is exactly what could be expected from somebody with autoantibodies in his blood serum. I really think there is something there.

Well---it may be, Frodo. But the benefit of plasmapheresis in MS is not proven to be antibody related....it could be about coagulation factors, fibrinogen levels, proteins or other factors.
Anticoagulation is a large part of plasmapheresis
http://www.neurology.org/content/47/3/840.full
And plasmapheresis, although effective in antibody removal in serum, doesn't change antibodies in CSF--

Treatment with plasmapheresis may fail in patients with multiple sclerosis because it does not remove antibrain antibodies from the intrathecal space.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1416748/

I ascribe to the research of Dr. Michal Schwartz and the understanding of these antibodies as signs of the body's natural, protective autoimmunity.

Michal Schwartz’ studies revolutionized the current understanding of degenerative conditions of the central nervous system. Her theory not only broke long-held dogmas, but also shattered a conceptual wall between the brain and the immune system, which plays a fundamental role throughout life in supporting brain plasticity – with far-reaching clinical implications for behavior, cognition, stress, neurodegenerative and neurodevelopmental diseases. At Falling Walls, Schwartz explains the latest developments of her theory of “protective autoimmunity” that has inspired the search for new therapeutic strategies, harnessing or modulating immune cells to fight ageing, and acute and chronic neurodegenerative diseases.

A must watch video on this science, which is calling into question the autoimmune dogma.
http://falling-walls.com/videos/Michal-Schwartz-1646

KIR4.1 antibodies are also found in edema and hydrocephalus---when this water transport molecule becomes "mislocalized." The larger question is WHY? Not, how can we block this potentially healing antibody. WHY is it showing up? MS researchers need to be collaborating with other specialties, to ask the big questions.

cheer

cheerleader wrote:
As far as the Lucchinetti/Lesion Project research---Marc (Wheelchair Kamikazee) summed up what many on this board felt back in 2009 when I started a discussion on the Lesion Project--- http://www.thisisms.com/forum/general-d ... c6851.html

I've discussed the findings of The Lesion Project with a number of neurologists, and most of them are a bit skeptical of the findings. They say that even if a patient displays only one type of lesion postmortem, that does not mean that their lesions didn't evolve through different stages over time.

Going back to the previous topic, all I can say is that when neuros are skeptical, then it is probably true. (sorry. I have no better arguments)

That neurologists disagree may be the best of arguments. I think science is getting closer all the time, but they are so slow. What can be causing and worsening these venous lesions only in some people, and after varying amounts of successful, healthful, sometimes very hardy life with no sign of trouble from any such source?

cheerleader wrote: I'm hoping researchers look at the other situations where these KIR4.1 antibodies show up---in cerebral edema and hydrocephalus. There may be more clues in that line of research. http://ccsviinms.blogspot.com/2014/02/k ... cture.html

Hi Again, Cheer.

I am afraid that speak about Kir4.1 autoantibodies in the cases you report could be a mistake. I have been following the link you provided, and it does not say that Kir4.1 antibodies appear in these two diseases. They say that Kir4.1 proteins (not anti-kir4.1 antibodies) have some problems in cerebral edema and hydrocephalus. But autoimmunity is not reported to play a role in this cases. The site I checked out was:

http://ccsviinms.blogspot.com.es/2014/0 ... cture.html

In the first case they clearly say:

In pathological brain tissue, AQP4 was upregulated in astrocytes in oedematous regions and Kir4.1 was upregulated in astrocytes in damaged brain.

In the second case is less clear. They say:

Kir4.1, a potassium channel protein linked to water flux, exhibited enhanced immunoreactivity in the cerebral cortex of hydrocephalic rats; the perineuronal distribution was entirely different from that of AQP4

This could mean that an antibody was found, but they can also be speaking about some lab test about immunireactivity, as they say "Gemistocytes in glioblastoma showed pronounced Kir4.1 immunoreactivity". I don't understand the meaning, but it looks like they were speaking about a lab test.

If this were the case, MS cases would still be the only ones in which autoimmunity against kir4.1 has been found.

Of course, this means that Kir4.1 protein is important for brain normal function, and that misbehaviour in its development or autoimmune attacks against it produce similar problems, but nothing else can be inferred from these reports.

http://falling-walls.com/videos/Michal-Schwartz-1646 which cheerleader refers to, does not just question autoimmunity, it goes farther, and says that compromise, (not enhancement) of auto-immunity is the cause of cognitive deficit in brain diseases and even in pregnancy. By enhancing the immune systems of mice they were able to cure peripheral problems. in addition, in immune-compromised individuals (such as those on Rebif?) there is loss of the benefit of exercise, perhaps because of the suppression of those immune cells which are not gated by the BBB, but gated by the Brain-CSF-Barrier. These cells are still affected when the whole system gets compromised. This happens in pregnancy, PTSD, and degenerative brain disease, where anti-inflammatory therapies do not work.

There are more reports about sera (I assume they mean blood serum) involvement in MS development. It seems that they have taken serum from MS patients and they have put it into a culture of vascular tissues. They have found that a protein (VCAM-1) increases, and that breaks the BBB.

For me, this discovery means that, for at least a subtype of MS patients, their disease is not due to CCSVI.

Article: http://www.ncbi.nlm.nih.gov/pubmed/24686948

Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier.

BACKGROUND:
Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients.

METHODS:
We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R), stable phase of RRMS (RRMS-S) and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs).

RESULTS:
Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, the immunoglobulin G (IgG) purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs.

CONCLUSIONS:
The up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.

What is in the sera that causes the increased vCAM-1? The conductance changes? I thought I'd read a paper by Simka et al that said changes in the shear force of venous blood is upregulating VCAM-1. This makes sense when flow isn't up to snuff, let the leukocytes in...