Autoantibodies to the glutamate receptor kill neurons via activation of the receptor ion channel

Antibodies to the glutamate/AMPA receptor subunit 3 (GluR3), are found in a human epilepsy, Rasmussen's encephalitis [RE], and were hypothesized as th e major cause for the neuronal loss, chronic inflammatory changes and epile ptic seizures characteristic of the disease. To establish the pathogenic po tential and mechanism of action of such antibodies, we raised murine antibo dies against specific peptides of the GluR3 protein and studied their abili ty to bind, activate, and kill neurons. Mice were immunized with two GluR3 specific peptides: GluR3A (amino acids 245-274) and GluR3B (amino acids 372 -395), and with a scrambled GluR3B peptide for control. High levels of anti bodies to each of these peptides were obtained, with no cross reactivity be tween them. Antibodies to the GluR3B peptide were found to bind to cultured neurons, evoke GluR ion channel activity, and kill neurons. Ln contrast, a ntibodies against GluR3A peptide bound to neurons but failed to activate th e receptor or kill neurons. Anti-scrambled-GluR3B antibodies had no effect. Both the activation of the GluRs and the neuronal death induced by anti-Gl uR3B antibodies were blocked by CNQX, a specific glutamate/AMPA receptor an tagonist; killing was independent of complement. This indicates a mechanism of excitotoxicity-neuronal death due to over-activation of the receptor, a phenomenon known to be caused by excess of glutamate. Purified anti-GluR3B IgGs retained the neuronal killing capacity, and killing was completely an d specifically blocked by preincubation with the GluR3B peptide. Excitotoxi c neuronal death induced by anti-GluR3B antibodies took place primarily via apoptosis. Taken together, these results show that antibodies to a specifi c peptide of the GluR can kill neurons by an excitotoxic mechanism, thus mi micking the effects of excess of glutamate. This is the first example that antibodies can lead to neuronal death in a non-classical complement-indepen dent manner, via activation of a membranal neurotransmitter receptor. (C) 1 999 Academic Press.