Water Channel Protein Implicated In Relative Of Multiple Sclerosis

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

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

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

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

This is particularly important for clinicians because specifictreatment recommendations to help prevent blindness and other latersymptoms, including paralysis, differ for NMO and MS .

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

The Mayo Clinic group's work reveals that the protein targetedby the NMO antibody is not a component of myelin, or ofoligodendrocytes. Aquaporin-4, which is the most abundant water channelin the brain, is instead located in a different type of cell calledastrocytes.

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

The next step in this research is to use this knowledge tocreate an animal model that can be used to confirm the relationhipbetween aquaporin-4 and NMO, as well as to develop new and improvedtherapies.

[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 NobelPrize in Chemistry, have not been implicated in many pathologicaldisorders, and never in an autoimmune neurological context. Our studyidentifies the mercurial-insensitive water channel protein, aquaporin4(AQP4), as the disease-specific autoantigen recognized by an IgG foundexclusively in serum of patients with neuromyelitis optica (NMO; 73%sensitive, >90% specific) and NMO-related disorders (includingrelapsing transverse myelitis and optic neuritis). Traditionallyconsidered a severe variant of multiple sclerosis (MS), and commonlymisdiagnosed (and inappropriately treated) as MS, NMO is confidentlydistinguishable from MS when this autoantibody is detected. AQP4 is thefirst autoantigen ever identified in the context of an idiopathicinflammatory demyelinating disorder of the central nervous system(CNS). Its molecular identification heralds development of the firstauthentic animal model for CNS demyelinating disease, and thence moreeffective therapies. The most conclusive experiments, involving thetransfection of a non-CNS cell line with the human AQP4 gene, and theselective precipitation of its expressed product from cell lysates byIgG in sera of patients with NMO, were commenced April 7, 2005.

Inflammatory demyelinating diseases of the central nervoussystem (CNS) are recognized to be immune-mediated, but nodisease-specific microbial antigen or autoantigen has been identified.Neuromyelitis optica (NMO) selectively affects optic nerves and spinalcord, and is considered a severe variant of multiple sclerosis (MS). Itis frequently misdiagnosed as MS, but prognosis and optimal treatmentsdiffer. We recently described an NMO-specific IgG in the serum of 73%of patients with NMO, and in 58% of patients with Asian optic-spinalMS. In patients with new onset transverse myelitis or optic neuritis,seropositivity predicts relapse or future development of NMO. Patientswith classical MS are seronegative. We initially reported from itsimmunostaining pattern that NMO-IgG binds to subpial elements and CNSmicrovasculature, colocalizing with laminin near the blood-brainbarrier (Lennon, Lancet, 2004). Here we report that,immunohistochemically, NMOIgG colocalizes precisely with theaquaporin-4 water channel (AQP4), and does not bind to CNS tissue ofAQP4-null mice. It binds selectively to AQP4-transfected non-CNS cells,and exclusively immunoprecipitates the AQP4 water channel component ofthe dystroglycan protein complex. We conclude that the autoantigen ofNMO-IgG is AQP4 in astrocytic foot processes. NMO may be the firstexample of a novel class of autoimmune channelopathy.