Autoimmune encephalitis and LGI1 autoantibodies : from B-Lymphocytes to antibodies
Leucine-rich Glioma-inactivated 1 (LGI1) and Contactin-associated Protein-like 2 (CASPR2) Autoimmune encephalitis (AIE) are neurological disorders characterized by immune-mediated brain inflammation. Despite advancements to understand these conditions, the precise mechanisms driving immune dysregulation remain elusive. This doctoral work presents a comprehensive investigation into LGI1 and CASPR2-AIE. First it is addressed the establishment of hippocampal neuronal cultures to study autoantibodies involved in AIE. This is particularly significant given the challenges associated with neuron culture, including low reproducibility. The study offers a simple and efficient procedure for obtaining hippocampal neurons while discussing limitations and the protocol's potential for identifying novel neuronal autoantibodies. These findings lay the foundation for future investigations and for the accredited use of this technique in routine health care. The subsequent projects focus on characterizing AIE from a cellular standpoint, aiming to evaluate the role of B cells in disease development and persistence. Initially, a technique for isolating anti-LGI1 antigen-specific B cells from peripheral blood was established. Despite challenges in protein purification, the study demonstrates the validity of this approach, prompting further exploration into the significance of antigen-specific B cells in the pathogenesis of AIE. Subsequently, clonally expanded B cells in the cerebrospinal fluid (CSF) of individuals with anti-LGI1 and anti-CASPR2-AIE were characterized, providing insights into antibody maturation and epitope recognition. These studies illuminate the complex mechanisms underlying AIE and offer valuable insights to enhance diagnosis and understanding of this debilitating condition. In conclusion, this thesis advances our understanding of AIE by employing different approaches encompassing cell culture techniques, antibody characterization, and immune profiling.
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