15 April 2003 15:00 GMT

by Laura Spinney

A disease of the central nervous system with symptoms that include memory loss and seizures is caused by the body producing antibodies against a key brain protein, British researchers report. They have found low levels of the same antibodies in some patients with intractable epilepsy - evidence which, combined with a large new study soon to be published, could strengthen the case for viewing some forms of epilepsy as autoimmune disorders.

Angela Vincent, an immunologist in the neurosciences group at the Weatherall Institute of Molecular Medicine in Oxford, and her colleagues tested the blood of ten patients suffering from the rare condition limbic encephalitis (LE), and found that nine of them were carrying antibodies against the protein that forms voltage-gated potassium channels (VGKC) in the neuronal membrane-ion channels crucial to the cell's normal functioning.

They went on to show that immunotherapies that reduced the VGKC antibody count in these patients also produced an improvement in their symptoms, suggesting the antibodies play a causal role in the disease.

Vincent believes that LE is an autoimmune disease that may or may not be triggered by an initial viral infection that has cleared up.

Because some epilepsy syndromes are related to genetic defects in ion channels, she wondered if a similar immune mechanism might give rise to epilepsy or epilepsy-like symptoms, by attacking those same ion channels. So she and her colleagues also tested 115 adults with drug-resistant epilepsy for antibodies to VGKC.

Nine subjects tested positive, although with low concentrations; eleven were found to be carrying antibodies to an intracellular enzyme called glutamic acid decarboxylase (GAD).

To demonstrate that VGKC antibodies are playing a pathogenic role in those nine cases, says Vincent, they would have to show that they bind to the extracellular domain of the VGKC, rather than the intracellular domain, something she is now testing.>

"We know that in some conditions you get antibodies to the inside of the VGKC, but those antibodies are usually secondary to damage and are not the primary cause," she told BioMedNet News.

Similarly, the antibodies to GAD, which is found inside the cell, are probably an effect rather than a cause of epilepsy-related brain damage.

 

But, she added, if the antibodies do turn out to bind to the outside of the VGKC, "One would seriously think of trying to treat some of those patients with steroids or other immune treatments."

 

Edward Cooper, a neurologist at University of Pennsylvania Medical Center in Philadelphia, says these are "very exciting and potentially quite important findings," although it is too early to draw any firm conclusions from them.

"An autoimmune mechanism for refractory epilepsy is especially intriguing because of the mysterious latent period that is a feature in many cases," he said.

Epilepsy can occur transiently in childhood, then recur after a period of remission in adolescence or adulthood.

"Slow autoimmune attack on brain channels might contribute to this common natural history in some patients," Cooper speculated.

But Mia Levite, a neurobiologist at the Weizmann Institute of Science in Rehovot, Israel and Tel Aviv University who first coined the phrase "autoimmune epilepsy," points out that this is the first time potassium channels have been implicated in the disease and that they don't seem to be the major players.

"The focus now is primarily on antibodies to the glutamate receptor of the AMPA ionotropic subtype 3," she said.

Levite's team is about to publish a large-scale study in which they have attempted to correlate different types of epilepsy with different types and concentrations of antibodies in patients' blood and cerebrospinal fluid.

The results are "solid" regarding these glutamate receptors, she hints, adding that, once they are published, clinicians will be forced to reassess their diagnostic and therapeutic strategies to allow for an autoimmune component in epilepsy. But she warns that direct evidence that antibodies by themselves can cause epilepsy is still lacking.L

Vincent presented her work on April 14 at a meeting of the British Neuroscience Association in Harrogate, UK.

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See also:
Autoantibodies to ion channels at the neuromuscular junction
Bethan Lang and Angela Vincent
Autoantibodies directed against voltage- or ligand-gated ion channels and their associated proteins at the neuromuscular junction give rise to a family of neurological autoimmune diseases. Antibodies to acetylcholine receptors or...
Autoimmunity Reviews, 2003, 2:2:94-100

The expanding world of autoimmunity [Meeting report]
Yehuda Shoenfeld, Yaniv Sherer and Joachim R. Kalden
The recent 3rd International Congress on Autoimmunity provides new evidence for the expansion of autoimmunity into areas that deal with pathogenic mechanisms, autoantigens and autoantibodies, therapeutic modalities and even new diseases. Autoimmunity involves practically every field in medicine.
Trends in Immunology, 2002, 23:6:278-279


Immune mechanisms in neurological disorders: protective or destructive? [Meeting report]
Kirsty Minton
The VIth Congress of the International Society of Neuroimmunology was held in Edinburgh, Scotland from 3-7 September 2001.
Trends in Immunology, 2001, 22:12:655-657
 

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