Epitopic targets of the monoclonal auto-antibody repertoire in autoimmune encephalitis

• Applicant: Professor Dr. Harald Prüß
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 389638682

Discovered only a few years ago, anti-NMDA receptor (NMDAR) encephalitis has become one of the most commonly identified causes of encephalitis and an important differential diagnosis for new-onset psychosis, characteristically associated with hallucinations, catatonia, altered levels of consciousness, seizures, hypoventilation, dyskinesia, and autonomic dysfunction. Auto-antibodies against the NMDAR are directly pathogenic by causing receptor internalization and synaptic dysfunction. We could recently generate monoclonal human NMDAR auto-antibodies from the cerebrospinal fluid of patients with this encephalitis by single-cell amplification, sequencing and cloning of full-length immunoglobulin heavy and light chain genes from memory B cells and plasma cells. The monoclonal NMDAR autoantibodies have quickly become invaluable tools for histological and electrophysiological assays and for high-resolution microscopy. Surprisingly, the majority of antibody-secreting cells in the brain of these patients produced antibodies against other, although brain-restricted, epitopes, such as astrocytes, axonal fiber tracts, hippocampal neuropil or granule cells, endothelium or choroid plexus. First identifications of target proteins suggest that they bind to key players of neuronal function, neurodegeneration and autoimmunity. In this way these additional auto-antibodies might be similarly pathogenic and can contribute to the variable clinical symptoms of the disease, potentially by interfering with ion channel or receptor function. Thus, the current proposal aims at the identification of the target proteins of the human cerebrospinal fluid auto-antibody repertoire in patients with encephalitis using immunoprecipitation and mass spectrometry. In addition, the findings will be compared to related forms of brain inflammation and to healthy controls. Data from this study will help to understand the causal relationship between autoimmunity and neuropsychiatric disorders, and potentially identify novel targets for the treatment of such conditions.

• DFG Programme: Research Grants