A new finding with implications for MS

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A new finding with implications for MS

Postby dignan » Wed Sep 21, 2005 1:37 pm

I'm not sure what the implications for MS are exactly, but I'm happy that somebody has found a new factor to consider in MS (a subset at least)



Water channel protein implicated in relative of multiple sclerosis

21 Sep 2005 - Researchers have identified a molecular suspect in a disorder similar to multiple sclerosis (MS) that attacks the optic nerve and spinal cord, according to a report presented at the 130th annual meeting of the American Neurological Association in San Diego. The protein, called aquaporin-4, is a channel protein that allows water to move in and out of cells.

"Aquaporin-4 is the first specific molecule to be defined as a target for the autoimmune response in any form of MS," said author Vanda A. Lennon, MD, PhD, of the Mayo Clinic in Rochester, Minnesota. "It is also the first example of a water channel being the target of any autoimmune disorder."

Because there are many other variants of aquaporins throughout the body, Lennon suggests that these proteins might play a role in poorly understood autoimmune disorders in other organ systems.

For some time, scientists have understood that multiple sclerosis is not so much a single disease, but a category of disorders with similar damage to different parts of the nervous system. Recently, progress has been made in teasing out a particular syndrome called neuromyelitis optica (NMO), in which the body mistakenly mounts an immune attack against the optic nerve and spinal cord.

Last year, Lennon and her colleagues at Mayo, along with collaborators in Japan, were able to detect a particular antibody that occurrs in most people with NMO, but not in patients with "classical" MS.

This is particularly important for clinicians because specific treatment recommendations to help prevent blindness and other later symptoms, including paralysis, differ for NMO and MS.

In the present study, Lennon and colleagues have identified an aquaporin as the target molecule of the NMO antibody. "This finding is a departure from mainstream thinking about MS and related disorders, where the major focus of research in the past century has been the myelin that insulates nerve fibers, and the cell that manufactures myelin, known as the oligodendrocyte," said Lennon.

The Mayo Clinic group's work reveals that the protein targeted by the NMO antibody is not a component of myelin, or of oligodendrocytes. Aquaporin-4, which is the most abundant water channel in the brain, is instead located in a different type of cell called astrocytes.

"Aquaporin-4 is concentrated in membranes in the precise site where spinal cord inflammation is found in NMO patients," said Lennon.

The next step in this research is to use this knowledge to create an animal model that can be used to confirm the relationhip between aquaporin-4 and NMO, as well as to develop new and improved therapies.

[Background/Abstract]

Autoantibody Marker of Neuromyelitis Optica Binds to the Aquaporin-4 Water Channel

Vanda A. Lennon MD, PhD, Thomas J. Kryzer, Sean J. Pittock, A.S. Verkman, Shannon R. Hinson, Rochester MN

Water channel proteins, which were the subject of the 2003 Nobel Prize in Chemistry, have not been implicated in many pathological disorders, and never in an autoimmune neurological context. Our study identifies the mercurial-insensitive water channel protein, aquaporin4 (AQP4), as the disease-specific autoantigen recognized by an IgG found exclusively in serum of patients with neuromyelitis optica (NMO; 73% sensitive, >90% specific) and NMO-related disorders (including relapsing transverse myelitis and optic neuritis). Traditionally considered a severe variant of multiple sclerosis (MS), and commonly misdiagnosed (and inappropriately treated) as MS, NMO is confidently distinguishable from MS when this autoantibody is detected. AQP4 is the first autoantigen ever identified in the context of an idiopathic inflammatory demyelinating disorder of the central nervous system (CNS). Its molecular identification heralds development of the first authentic animal model for CNS demyelinating disease, and thence more effective therapies. The most conclusive experiments, involving the transfection of a non-CNS cell line with the human AQP4 gene, and the selective precipitation of its expressed product from cell lysates by IgG in sera of patients with NMO, were commenced April 7, 2005.

Inflammatory demyelinating diseases of the central nervous system (CNS) are recognized to be immune-mediated, but no disease-specific microbial antigen or autoantigen has been identified. Neuromyelitis optica (NMO) selectively affects optic nerves and spinal cord, and is considered a severe variant of multiple sclerosis (MS). It is frequently misdiagnosed as MS, but prognosis and optimal treatments differ. We recently described an NMO-specific IgG in the serum of 73% of patients with NMO, and in 58% of patients with Asian optic-spinal MS. In patients with new onset transverse myelitis or optic neuritis, seropositivity predicts relapse or future development of NMO. Patients with classical MS are seronegative. We initially reported from its immunostaining pattern that NMO-IgG binds to subpial elements and CNS microvasculature, colocalizing with laminin near the blood-brain barrier (Lennon, Lancet, 2004). Here we report that, immunohistochemically, NMOIgG colocalizes precisely with the aquaporin-4 water channel (AQP4), and does not bind to CNS tissue of AQP4-null mice. It binds selectively to AQP4-transfected non-CNS cells, and exclusively immunoprecipitates the AQP4 water channel component of the dystroglycan protein complex. We conclude that the autoantigen of NMO-IgG is AQP4 in astrocytic foot processes. NMO may be the first example of a novel class of autoimmune channelopathy.

http://www.medicalnewstoday.com/medical ... wsid=30974
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Re: A new finding with implications for MS

Postby NHE » Wed Sep 21, 2005 7:05 pm

Dignan wrote:Inflammatory demyelinating diseases of the central nervous system (CNS) are recognized to be immune-mediated, but no disease-specific microbial antigen or autoantigen has been identified.

This statement is confusing. I thought that MS autoantigens have already been discovered, e.g., myelin oligodendrocyte glycoprotein, proteolipid protein, and myelin basic protein? Without these known autoantigens, it would seem that treatments such as Tovaxin would not be possible.

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Postby OddDuck » Fri Sep 23, 2005 3:46 am

NHE,

The key words there are "disease-specific".

What they are saying is that even though those things you mentioned have been "implicated" as "maybe" being involved somehow, they haven't identified one that is "disease-specific", i.e. that is the CAUSE of MS.

They haven't identified what causes or definitively contributes to the cause of MS. That's all it means.

Plus, some of the things you mention may also be involved in other diseases besides MS, so again they are not considered "disease-specific".

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Re: A new finding with implications for MS

Postby NHE » Fri Sep 23, 2005 11:38 pm

OddDuck wrote:They haven't identified what causes or definitively contributes to the cause of MS. That's all it means.

I guess I'm confused. Tovaxin is an experimental T-cell vaccine which trains the immune system to target T-cells which specifically react against the three myelin proteins I listed, i.e., MOG, PLP, & MBP. By eliminating these myelin reactive T-cells, PharmaFronteirs sites a 90% reduction in relapses. The three proteins do indeed appear to be autoantigens which contribute to the MS pathology.

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Postby Melody » Sat Sep 24, 2005 3:27 am

Katherine Conant, MD

Pilot Research Award: 7/1/05 to 6/30/06 $44,000

“Aquaporin 4 in multiple sclerosis” Investigating whether excesses of a certain protein in people with MS plays a role in enabling the immune attack.


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Re: A new finding with implications for MS

Postby NHE » Sat Sep 24, 2005 4:59 am

Melody wrote:Katherine Conant, MD
Pilot Research Award: 7/1/05 to 6/30/06 $44,000

Thanks for the info Melody. Here's a link with more information
http://www.nationalmssociety.org/Research-Conant.asp

However, unlike the autoimmune reaction discovered for neuromyelitis optica, the above study is focussing on the channel's activity and regulation.
Multiple sclerosis occurs when the immune system attacks the brain and spinal cord. Astrocytes are the most numerous cells in the brain, providing critical support to the blood-brain barrier (BBB, a layer of tight cells that line blood vessels, and normally prevents most immune cells from entering the nervous system). Their ability to provide support may depend on their shape; swollen cells may be less capable of supporting this barrier. Katherine Conant, MD, is investigating how astrocyte function may go awry in MS.

Specifically, Dr. Conant is studying a protein called “aquaporin 4.” Aquaporins are proteins that allow for the passage of water. If aquaporins are overly active, cells might swell. Aquaporin 4 is active in astrocytes. Dr. Conant is studying brain tissue from people with MS and controls without MS to compare the activity of aquaporin 4. She also is using rat cell cultures to determine how altering aquaporin 4 activity alters the activity of cells taken from the BBB.

It seems that this research group believes that there may be a problem with cell volume regulation with the cells forming part of the blood-brain barrier. It is interesting that they would target an aquaporin. Water typically flows down an osmotic gradient which is established by other means, e.g., ion channels or exchangers or via the breakdown of certain proteins releasing free amino acids or other monomeric units or by some change in the extracellular osmolarity. Without this osmotic gradient, there should be no net driving force for the movement of water. Something seems awry or did I miss something?

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