Mayo Scientists Identify Target for Antibody Defining Severe Form of Multiple Sclerosis

Thursday, August 18, 2005

Mayo Clinic researchers have discovered the protein targeted by an antibody that distinguishes a severe form of multiple sclerosis (MS), known as neuromyelitis optica (NMO), or Devic's disease. The more common forms of MS are generally less severe. This distinction is important because treatments differ for NMO and MS, and early appropriate treatment optimizes the chance for a good recovery from NMO and can help avoid recurring episodes of blindness, paralysis, painful spasms, loss of sensation and incontinence.

The Mayo team's report appears in the current issue of the Journal of Experimental Medicine (opens in new window). It follows on the heels of the team's major discovery last year of the NMO antibody (reported in the December 2004 issue of The Lancet). Since that report, the NMO antibody is proving to be a valuable blood test that physicians can use to diagnosis NMO in its early symptom stage.

A Novel Class of Proteins

The target of the NMO antibody is a member of an entirely novel class of proteins that allow water to move in and out of cells called water channels or 'aquaporins.'

"This finding is a departure from mainstream thinking about inflammatory demyelinating diseases, because the major focus of MS research in the past century has been the myelin that insulates nerve fibers and the cell that manufactures myelin, known as the oligodendrocyte-type glial cell," says Vanda Lennon, M.D., Ph.D., Mayo Clinic neuroimmunologist and lead researcher on the study. "The Mayo Clinic Neuroimmunology Laboratory's finding is groundbreaking because it reveals that the protein targeted by the NMO antibody is not a component of myelin, nor is it a component of the oligodendrocyte-type glial cell; it's an aquaporin."

Biological Background

The specific target of the NMO antibody is called aquaporin-4 (AQP4) and is the most abundant water channel in the brain. AQP4 is located in the astrocyte-type glial cell that supports nerve cells and is concentrated in membranes that line the blood-brain barrier. This lining is the precise site where spinal cord inflammation is found in NMO patients. AQP4 is the first specific molecule to be defined as a target for the autoimmune response — an immune response against self — occurring in patients with any form of MS.

"We have no idea what causes the antibodies to be produced, but unlike MS, antibodies in NMO are produced outside the brain, and we have now shown fairly conclusively — and for the first time — what the antibodies bind to in the brain," says Dr. Lennon. "The water channel molecule itself is in all human brains. But the antibodies are made only in patients with NMO, and we believe these antibodies cross the blood-brain barrier to cause symptoms of NMO. An unanswered question at this time is why this disease selectively affects the spinal cord and optic nerves in a majority of cases."

About NMO

Neuromyelitis optica is a recurring debilitating inflammatory disease that leads to destruction of the protective myelin sheath around the optic nerve and the spinal cord. This ultimately leads to impaired vision, including blindness; impaired mobility; and loss of bladder and bowel control. Within five years, half of NMO patients lose vision in at least one eye or the ability to walk independently. Its cause is unknown, and its prognosis is generally poor, though early diagnosis can improve that. If diagnosed correctly before the myelin sheath is too damaged, plasma exchange therapy and immunosuppressive medications such as azathioprine and corticosteroids can effectively stop the damage and restore nerve function.

The prognosis for loss of sight and permanent paralysis is much worse for patients with NMO than for those with MS. The symptoms of the two diseases overlap, and optic nerve and spinal cord involvement occur in both, but MS affects other areas of the brain, too. NMO is particularly difficult to distinguish from MS in the early phases of the disease.

In Japan, NMO accounts for one-third of cases diagnosed as MS. Though it is considered rare in the United States, Mayo researchers believe it is underreported because it so frequently gets confused with the standard form of MS. The diagnostic blood test Mayo researchers developed to detect NMO antibodies now helps NMO patients receive both the correct diagnosis and best treatment early.

The Next Step

The next step is to develop and validate the accuracy of an animal model of the NMO form of MS by immunizing laboratory animals with the AQP4 protein. This step will allow researchers to precisely gauge the effect of AQP4 on the development of the disease, and in so doing, provide ultimate proof of a cause-and-effect relationship between the AQP4 antibody and this severe form of MS. An authenticated animal model should expedite the development of superior and more specific therapies — and perhaps, ultimately, a cure for NMO and related diseases that are still being defined.

Collaboration and Support

In addition to Dr. Lennon, the research team included Thomas Kryzer; Sean Pittock, M.D.; and Shannon Hinson, Ph.D. They collaborated with Alan Verkman, M.D., Ph.D., at the University of California, San Francisco. Their work was supported by Mayo Foundation.
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