Water channel protein implicated in relative of multiple sclerosis

September 21, 2005

San Diego -- 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.

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.

American Neurological Association

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