Clinician Scientist-Programm OrganAge 2021

Thema: "Creating an active immunization model of LGI1 encephalitis"

Zusammenfassung:
Autoimmune encephalitis (AE) is a group of inflammatory brain diseases characterized by neuropsychiatric symptoms, seizures and cognitive deficits. Subtypes of AE are associated with autoantibodies against neuronal cell surface proteins or receptors. The most frequent subtype of AE representing as limbic encephalitis is the LGI1 encephalitis, clinically characterized by faciobrachial seizures and severe cognitive deficits followed by progressive hippocampal atrophy. Previous findings, including our own suggested direct pathogenicity of LGI1 autoantibodies using passive transfer animal models with purified IgG derived from patients of LGI1 encephalitis. However, these passive-transfer models are only incompletely representing the complex pathophysiology of the disease. An active immunization mouse model is still missing which allows studying short and long-term effects of antibodies and finally proving the Koch-Witebsky criteria of an autoimmune disease. Furthermore, the underlying immune-mediated mechanisms remain unclear, in part of a lack of a suitable animal model. Our aim is to develop and characterize a mouse model of LGI1 encephalitis using active immunization with the antigen and functionally relevant protein domains. For immunization purposes we will use full-length LGI1 and a LGI1 peptide packed in liposomes as recently described for the NMDA receptor encephalitis mouse model. Using behavioral, electrophysiological and methods of molecular biology we will uncover pathomechanisms of disease and we will evaluate long-term effects on cognition. Development of an LGI1 encephalitis animal model will lead to better understanding of the role of the immune system in the disease, the pathophysiology of the antibody, and eventually lead to better therapies.