It only takes seconds for a human monoclonal autoantibody to inhibit N-methyl-D-aspartate receptors
Transfer of autoantibodies targeting ionotropic N-methyl-D-aspartate receptors in autoimmune encephalitis patients into mice leads to typical disease signs. The long-term effects of receptor internalization significantly influence the antibody response. In this study, we focus on the direct and immediate impact of a specific patient's autoantibody on the function of N-methyl-D-aspartate receptors. We performed cell-attached single-channel recordings in human embryonic kidney cells transfected with the GluN1 and GluN2A subunit of the N-methyl-D-aspartate receptor. We investigated the direct effects of a specific and well-characterized monoclonal patient autoantibody (immunoglobulin G #003-102) against the amino-terminal domain of the glycine-binding GluN1 subunit of the receptors. Immunoglobulin G #003-102 reduced simultaneous receptor openings significantly compared to the control immunoglobulin G at both low and high glutamate and glycine concentrations. Upon closer examination of our data in 50-second to 2-second intervals, it is evident that the presence of autoantibodies results in a rapid decrease in the number of open receptors. On the other hand, the presence of antigen-binding fragments of immunoglobulin G #003-102 did not reduce the receptor openings. In conclusion, monoclonal immunoglobulin G #003-102 inhibits N-methyl-D-aspartate receptors rapidly and directly before receptor internalization occurs. The corresponding antigen-binding fragments did not alter the channel activity, indicating that the entire immunoglobulin G is necessary for the acute inhibitory effect. These results suggest an application of the antigen-binding fragments of #003-102 as a potential new treatment strategy for shielding the pathogenic epitopes on the N-methyl-D-aspartate receptors.