Limbic encephalitis: autoantibodies trigger overexcitation in the brain

A growing number of psychiatric and neurological diseases are based on antibodies that are not being directed against pathogens but rather against the body's own proteins in the brain. This had led to a group of conditions known as autoimmune encephalitis. How the antibodies trigger the symptoms of these conditions, however, is still barely understood. A current research project underway at the German Center for Neurodegenerative Diseases (DZNE), in cooperation with the NeuroCure Cluster of Excellence at Charité-Universitätsmedizin Berlin, suggests that individual antibodies from the cerebrospinal fluid of patients with limbic encephalitis, a certain form of autoimmune encephalitis, increases the excitability of nerve cells. This finding moves us in the direction of a better understanding of the disease. The results have been published in the journal Annals of Neurology* (Ann Neurol 2020; 87: 405-418).

Patients with limbic encephalitis suffer from epileptic seizures, confusion, personality changes, and dementia. Often the diagnosis of limbic encephalitis is based on the detection of antibodies against a specific protein called LGI1 (leucine-rich glioma-inactivated protein 1), which attaches itself to specific sites on the surfaces of nerve cells. Removal of these antibodies by blood dialysis and immunotherapy often leads to successful treatment, or in some cases even to a cure. Still, little is known about the exact mechanism by which this takes place.

At the Charité-Universitätsmedizin and the DZNE in Berlin, a group of scientists and physicians have come together with Prof. Dr. Harald Prüß and Prof. Dr. Dietmar Schmitz to research the autoimmune processes in the brains of patients with limbic encephalitis. The research group, led by the neurologist Prof. Prüß, has established a method that enables the isolation of individual immune cells from the cerebrospinal fluid. The antibodies produced by the immune cells can then be produced on a large scale. Dr. Hans-Christian Kornau, the first author on the study, used this method to obtain a total of 26 LGI1 antibodies from three patients with limbic encephalitis and examined those antibodies in detail.

A key question is how LGI1 antibodies can affect nerve cells. Dr. Alexander Stumpf from Prof. Schmitz's research group carried out electrophysiological recordings of nerve cells in prepared sections of the brain, and in so doing, was able to show that LGI1 antibodies significantly increase the excitability of the nerve cells. Cells incubated with an LGI1 antibody could be stimulated remarkably easily to transmit stimuli. Further experiments showed that the effect of the LGI1 antibodies was based on a reduction in potassium ion currents. Potassium ions normally attenuate the activity of nerve cells. When nerve cell populations in the brain of patients become active due to the LGI1 antibodies, even through subliminal stimuli, overexcitation can quickly spread and cause malfunctions.
 
"We want to understand how limbic encephalitis causes damage to the brain. The increased excitability of the nerve cells by the LGI1 antibodies could play a key role in this process," said Kornau. Prüß adds: "The study already provides outstanding scientific evidence that LGI1 antibodies are disease-causing and that our patients therefore require rapid and effective immunotherapy."

Contact:
Dr. Hans-Christian Kornau & Prof. Harald Prüß
German Center for Neurodegenerative Diseases (DZNE) Berlin
C/O Charité-Universitätsmedizin Berlin 
Email: Hans-Christian.kornau(at)dzne.de
Email: Harald.pruess(at)charite.de
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