AntibodyOMICs in CASPR2 Encephalitis

• Applicant: Professor Dr. Jan Lünemann
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505566873

Antibody (Ab)-mediated autoimmune encephalitides (AE) constitute a group of inflammatory brain diseases that are characterized by prominent neuropsychiatric symptoms and are associated with Abs against neuronal cell-surface proteins, ion channels, or receptors. Although the diagnosis is straightforward in most patients with typical symptoms and a positive Ab test, the phenotype of the disease and its clinical course including the response to immunotherapy is remarkably heterogeneous. Newly approved, or pending approval, therapies with biologics are increasingly available, and targeted immunotherapy has the potential to overcome limitations of current nonspecific immunotherapies and to induce long-term remission. Thus, there is urgent need for AE-related biomarkers predicting or defining clinical severity, clinical course and therapy-induced clinical benefits. Contactin associated protein-like 2 (Caspr2) encephalitis is a rare but paradigmatic neuronal surface Ab-mediated AE. While adoptive transfer of Caspr2-specific IgG induces neuropathology and clinical disease in susceptible rodents, the mechanisms by which Caspr2-Abs mediate pathology and how Ab-mediated effector functions translate into clinical syndromes and disease progression are incompletely understood. In the proposed research, we aim to profile pathogenic effector functions of Abs specific for Caspr2 and to identify signatures predictive for the clinical course and response to immunotherapy in patients with Caspr2-Ab associated AE. To this end, we will develop and employ a systems-level antibodyOMICs approach which includes a diverse constellation of cell types and functions, combining innate and adaptive immune features. Experimental data and clinical features will be analyzed using univariate, multivariate and machine learning-based algorithms. In vivo pathogenicity of human Caspr2-specific antibody variants characterized by aforementioned technologies will additionally be tested by adoptive transfer experiments in preclinical humanized mouse models of Caspr2-AE. The proposed collaborative research might not only provide novel fundamental insights into effector and regulatory mechanisms of encephalitogenic Abs and how these translate into clinical phenotypes but also aid the development of personalized medicine for the benefit of patients with Caspr2-Ab associated disease.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professorin Friederike Jönsson, Ph.D.