Project Details
Projekt
Origin and diversity of pathogenic human monoclonal antibodies to the NMDA receptor
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2019 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 415914819
In anti-NMDA receptor (NMDAR) encephalitis, autoantibodies against the GluN1 subunit of the NMDAR cause a distinct neuropsychiatric syndrome. We recently cloned the first human monoclonal GluN1 autoantibodies from cerebrospinal fluid plasma cells of NMDAR encephalitis patients. The antibodies induced synaptic pathology similar to patient-derived IgG. So far, it is unclear how the humoral autoimmune response is triggered, whether antibody-producing cells develop in the periphery and migrate into the brain, and whether individual autoantibodies differ in their pathogenic potential depending on the degree of affinity maturation or their biophysical properties. Here, we will investigate the origin of antibody-producing cells in NMDAR encephalitis by functional comparison of serum and cerebrospinal fluid-derived B cells at single-cell level through antibody cloning and expression. Specifically, we will investigate if the monoclonal antibodies react with synaptic targets in primary neurons, in human induced pluripotent stem cells (iPSC), and in brain sections. Furthermore, we will determine their affinity and their pathogenic effect upon passive-transfer in mouse models. We will further assess whether viral infections or tumors leading to secondary autoimmune encephalitis encompass anti-NMDAR antibody repertoires. Using our established single-cell cloning techniques, we also aim to identify disease-causing antibodies from other subtypes of autoimmune encephalitis, such as encephalitis with anti-GABAB receptor antibodies and with anti-LGI1 autoantibodies.
DFG Programme
Research Units
