Speaker: Dr. Josep Dalmau
Subject: Autoimmune encephalitis: from human disease to animal models
Location: Erasmus MC, Rotterdam
Author: Romano van Genderen
Dr. Josep Dalmau began to talk about an illusive disease in the brain, called autoimmune encephalitis. This is a disease of which in many cases the cause is unknown. A patient with a form of this disease has a certain mutation which makes his or her immune cells produce antibodies against their own neurons. There are three different types of this disease.:
1. Intracellular, in which the antibodies attack the intracellular proteins. This almost always causes the formation of tumours.
2. Synaptic intracellular, in which not the main cell body of the neuron, but only the synapses are affected.
3. Synaptic/surface, in which there are antibodies produced against proteins on the cell surface. This is the form with the most intense sickness, but often spontaneous recovery.
The one Dr Dalmau talked about was a synaptic form with antibodies against the NMDA receptor, a glutamate receptor on the synapse. Glutamate is the most common excitatory neurotransmitter in the human nervous system.
Image 1: The position and function of the NMDA receptor
This is why it has such massive clinical effects, such as psychosis and seizures. In extremely heavy cases this can lead to the patient entering a coma. But upon recovery the patient surprisingly enough remembers next to nothing about the period they had the disease. Sampling the patient database showed a few significant trends, such as the fact that the most common patients are adolescent females, which in 50% of the cases develop visible tumours. Another fact is that for younger patients there is no correlation between gender and the number of patients, and that young individuals never develop tumours.
One part of the talk that was interesting for me as a nanobiologist was how the changes in neuron function are caused by the anti-NMDA antibodies. It targets the post-synaptic glutamate receptors and removes them without having any effect on the voltage-gated potassium channels. Let me compare this to a power cable. You can stop the electricity from running through said cable in 2 ways, by pulling out the plug and by cutting the wire. The anti-NMDA antibodies do the first. They stop the incoming signal, but do not prevent the conduction.
One of the potential causes of the disease is the Herpex simplex virus. In order to investigate this, they used PCR to check for viral DNA in the patient’s brain, but this was not found. Therefore they concluded that the disease follows the viral infection, and is not a symptom of the infection.
The final part of his talk was how he used mouse models to investigate the disease. He slowly injected patient CSF (cerebral spinal fluid, the fluid that surrounds the brain) into mice. He used mice which were slowly injected with healthy patient CSF as a control. These results showed that the mice which were injected with patient CSF had memory loss, were anhedonic (unable to experience pleasure) and depressed, all checked using the standard procedures for mouse models. It also showed that ephrin-B2 prevented most of the symptoms. Using single molecule methods he found that it does not prevent the binding of the antibody, but it does prevent the effects.
This talk has shown me how modern experimental approaches, like PCR and single-molecule investigations, can shed light on unknown details of diseases, bringing mankind closer to finally discovering a cure.