NEWS - Immune antibodies and lupus-related memory loss

[Guest guest]

Weill CU scientist: Immune antibodies may be key to lupus-related memory

loss

By Ernie Mundell

NEW YORK For years, experts have puzzled over the fact that lupus patients

often experience accelerated declines in thinking and memory as they age,

despite the absence of the usual neurological culprits, such as

neurovascular inflammation or stroke.

Now a husband-and-wife-led team of researchers, including Dr. Bruce T.

Volpe, professor of neurology and neuroscience at Weill Cornell Medical

College and an attending neurologist at NewYork Presbyterian Hospital and

Burke Medical Research Institute in White Plains, say they have a new

approach to this puzzle that may open the door to treatments that slow or

prevent lupus-related cognitive decline.

An immune system antibody that lingers in especially high concentrations in

lupus patients appears to attack and kill brain cells, Volpe's team reports

in the journal Immunity.

" There may be an approach to attenuating the effect of the antibody,

however, " he said.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that causes

inflammation, pain and tissue damage throughout the body. Often chronic, it

affects mainly women. There is currently no cure for lupus, although

treatments can ease symptoms.

As treatments lengthened the lives of lupus sufferers, doctors began to

notice increased cognitive decline in many of their aging patients. However,

the brain cell death found in these patients wasn't always linked to

expected causes, such as stroke or inflammation.

Volpe said his work was spurred by a " brilliant " discovery a few years ago

by his wife, Dr. Betty Diamond, of Albert Einstein College of Medicine in

New York. Her team identified a specific autoimmune antibody, called

anti-NR2, which has a special affinity for glutamate receptors lying on the

surface of neurons and other cells.

Healthy individuals usually rid themselves of most of these auto-antibodies,

but Diamond found high blood concentrations of the antibodies in 40 to 60

percent of lupus patients. In his team's most recent study, Volpe used a

mouse model to determine just how these antibodies breach the blood-brain

barrier, allowing them access to healthy neurons.

" The temporary inflammation you can get during a cold, the flu or lupus

flare-up can 'open the gate' for antibodies to cross the blood-brain

barrier, " he explained, so the mice received an inflammation-inducing

compound to mimic that process.

Seven days after this inflammation occurred, the brains of mice that were

immunized to produce high concentrations of anti-NR2 " had already lost

significant numbers of neurons, especially in the hippocampus, but also

elsewhere throughout the cortex, " Volpe said. Behavioral tests, performed by

Dr. Patricio Huerta of New York University, suggested the mice still

functioned well in terms of motor skills but had suffered memory declines.

Now that the researchers knew lupus-linked auto-antibodies were attacking

and killing brain cells, could they find a way to stop it?

In another experiment, the multi-institutional team from Weill Cornell and

Einstein injected antibody-laden mice with memantine, a drug that competes

with the antibody for a parking space on each neuron's glutamate receptor.

The treatment stopped the antibody binding.

" When the memantine was injected, we stopped the neuron's stress response,

and we think it might have effectively preserved the neuron by interrupting

the auto-antibody's access to the receptor, " Volpe said. " More tests are

required before we approach treating humans, but this approach could lead to

new ways of slowing or stopping the cognitive decline seen in many older

lupus patients. "

The study has even broader implications, casting the immune system as a key

player in yet other disease processes, this time targeted neurological

damage. " The idea is that these antibodies may affect cognition -- they

certainly do in mice, " Volpe said.

The next step, he said, is to use MRI technology to determine the exact

permeability of the blood-brain barrier when it comes to anti-NR2

antibodies. Further experiments will also look closer at " just how the

antibody binds and kills, " he said, and what might be done to prevent that.

The study received funding from the National Institutes of Health, the Lupus

Research Institute, the Burke Medical Research Institute and the Pew

Foundation for Latin American Fellows.

Co-researchers on the study included Lorraine A. DeGiorgio of Burke Medical

Research Institute and Weill Cornell Medical College; Dr. Betty Diamond, Dr.

Hoby Hetherington, Czeslawa Kowal and Tsukasa Nakaoka of Albert

Einstein College of Medicine; and Dr. Patricio T. Huerta of the Center for

Neural Science, New York University.

September 16, 2004

http://www.news.cornell.edu/Chronicle/04/9.16.04/immune_antibodies.html