Autoimmune encephalitis: from human disease to animal models

Speaker:                     Josep Dalmau

Department:             Neuroscience

Subject:                      Autoimmune encephalitis: from human disease to animal models

Location:                    Erasmus MC Rotterdam

Date:                           07-09-2015

Author: Katja Slangewal

A shaking woman, her eyes wide open, she doesn’t respond at all to the touch of a doctor. We look at a short movie of a woman with autoimmune encephalitis. With 20.000 hospitalizations a year in the USA, this is a very serious disease. The disease is caused by autoimmunity; which means that antibodies are produced that attack the own body cells. Josep Dalmau specifically focuses on Anti-NMDAR encephalitis, in this specific disease the antibodies attack the NMDA receptor on the synapse. See figure 1. The antibodies disrupt the interaction between the NMDA receptor and another receptor called ephrin B2. This causes a decrease of inhibitory synapse density and it impedes signaling between neurons. Patients will notice this in form of the following symptoms: headaches, behavior changes, increased agitation, paranoia, seizures, abnormal movements, impaired cognition, memory loss and speech problems. When it gets worse patients will get in coma and suffer hypoventilation and dysautonomia. So anti-NMDAR encephalitis is truly a disease you would rather avoid.

Figure 1

Figure 1: Antibodies attack the NMDA receptor, NR1 and NR2 are subunits of the NMDA receptor.

Anti-NMDAR encephalitis is part of the synaptic surface subgroup of autoimmune encephalitis, which means the affected proteins are localized on the synaptic surface. In contrary to other more researched subgroups, the patients in the synaptic surface group don’t always carry tumors in their heads and are relatively young. This is useful to know while determining a cure. The search for a tumor would be a waste of time for these people for instance.

The precise cause of anti-NMDAR encephalitis is not entirely clear, though infection with the herpes simplex virus 1 (HSV1) could start the disease. Patients with HSV1 encephalitis (HSE) can produces antibodies against the NMDA receptor. These patients develop choreathetosis post-HSE which is seen as the same disease as anti-NMDAR encephalitis. Though HSE and anti-NMDAR encephalitis succeed each other, there are a lot of differences in detecting the disease. See table 1.

Tabel 1: difference between HSE and post-HSE

  Viral relapse of HSE Choreathetosis post-HSE
PCR Positive Negative
Abnormalities at MRI Yes No
Etiology Viral antibody

There are more uncertainties about anti-NMDAR encephalitis; one other question is for instance: how do the antibodies exactly start the disease? This is tested by using animal models, mice in this case. Antibodies are injected in a mouse and afterwards the effect is determined. These tests have shown that the antibodies are mostly found in the cerebrospinal fluid. A few days after the antibody injection, there is a clear loss of clustered NMDA receptors. The mice also show memory loss and depressive-like behavior, which is connected to the ephrin B2 receptor. Furthermore the tests show that the ephrin B2 doesn’t affect the binding of the antibodies. These facts gain by using animal models are import for the search to novel therapies.

Better therapies are needed not only for the people who suffer from anti-NMDAR encephalitis, but also for animals like polar bear Knut who also suffered from the disease. The work of Josep Dalmau hopefully helps to find those improved therapies.


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