Origin and Diversity of Pathogenic Human Monoclonal Antibodies and T cells in Tumor-associated Autoimmune Neurological Disorders

• Applicants: Professor Dr. Harald Prüß; Dr. Ilka Maria Wahl, since 11/2023
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 415914819

An increasing recognition of the role of autoantibodies in neurological diseases has markedly changed clinical practice in the field of neurology over the last decade. Pathogenic autoantibodies against NMDAR and further targets unraveled distinct disease mechanisms. Advancements in single-cell sequencing technologies allow for a more granular understanding of many different disease states, in particular the first steps of autoimmunity in autoimmune neurological syndromes. Here, using established single-cell sequencing approaches, we will investigate the origin and diversity of autoantibodies in tumor-associated autoimmune neurological syndromes including NMDAR encephalitis. We will compare B cell repertoires of different relevant compartments in patients, such as serum, cerebrospinal fluid and tumor, and further examine the pathogenicity of patient-derived antibodies. We will also assess the breadth of specificities of these autoreactive antibodies at monoclonal level by functional identification of potentially novel targets in an expanded scope of these disorders. Given the largely unexplored role of T cells in antibody-mediated encephalitides and after focusing on B cells in the first funding phase, we now extend the perspective to functional T cell receptor (TCR) repertoire analyses, and explore the role of T cells in shaping the humoral autoimmune response. Understanding the underlying immune mechanisms that lead to the development of autoimmune neurological syndromes will be essential to develop targeted prevention and therapeutic strategies.

• DFG Programme: Research Units
• Subproject of: FOR 3004: Synaptic pathology in autoimmune encephalitis – SYNABS
• Ehemalige Antragstellerin: Professorin Dr. Hedda Wardemann, until 11/2023