Researchers have identified a molecular suspect in a disorder similar to multiple sclerosis ( MS ) that attacks the optic nerve and spinal cord.
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 multiple sclerosis, " said author Vanda A. Lennon, of the Mayo Clinic in Rochester." 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" multiple sclerosis.

This is particularly important for clinicians because specific treatment recommendations to help prevent blindness and other later symptoms, including paralysis, differ for neuromyelitis optica and multiple sclerosis.

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 multiple sclerosis 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 relationship between aquaporin-4 and neuromyelitis optica, as well as to develop new and improved therapies.

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.

The 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 multiple sclerosis, NMO is confidently distinguishable from multiple sclerosis 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 ).

Source: American Neurological Association, 2005


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