Conference Agenda

The term Autoimmune encephalitis (AE) denotes a heterogeneous group of inflammatory disorders in which the host immune system targets self-antigens expressed in the brain. AE presents acutely or subacutely with memory loss, seizures, behavioral disturbances, and movement disorders such as choreoathetosis or dyskinesias.

In AE, Immunoglobulins G (IgG) autoantibodies bind to plasma membrane proteins critical for cell-to-cell communication in the Central Nervous System, including NMDAR, GABABR, and GABAAR.

The binding of IgGs to the ectodomain of target channels/receptors impair synaptic function directly (activating or preventing allosteric transition) or indirectly (inducing endocytosis/ degradation secondary to antigen crosslinking, or via inflammatory/cytotoxic sequelae of complement activation). Antibody testing plays an increasingly important role in the diagnosis of AE. Early recognition and treatment with immunotherapies are crucial for managing these relatively rare conditions effectively.

The presentation will provide an overview of the clinical manifestations and the immunopathogenesis of autoimmune encephalitis focusing on how synaptic autoantibodies alter synaptic transmission.

By bridging basic and clinical neuroscience, this presentation highlights the relevance of studying autoimmune encephalitis for both fields. Understanding the mechanisms of antibody-mediated synaptic dysfunction provides valuable insights into disease progression and offers potential avenues for novel therapeutic targets.

The discovery that autoantibodies targeting neural surface antigens can directly cause autoimmune encephalitis (AE) has brought about a paradigm shift in the field of autoimmune neurology, enabling the definition of entirely novel disease entities and ensuring their prompt diagnosis and treatment. Previous studies have characterized the functional effects of antibodies obtained from serum or cerebrospinal fluid (CSF) patient samples, providing evidence in support of their pathogenicity. However, this approach is limited by the paucity of patient material and its polyclonal nature, which prevents clear-cut conclusions about whether the observed structural and functional changes are caused by monospecific anti-neural antibodies.
The cloning and recombinant production of human monoclonal antibodies (mAbs) derived from the CSF B cells of AE patients have emerged as a key investigational tool to circumvent these limitations. This process enables the generation of disease-driving autoantibodies in theoretically unlimited amounts. This novel platform provided unprecedented insights into the CSF immunoglobulin repertoire of AE and led to the definitive proof of autoantibody pathogenicity both in vitro and in animal models, allowing their detailed functional characterization. Human mAbs targeting ion channels or essential synaptic proteins were shown to modulate neurons' electrophysiological functions and impair synaptic transmission through several mechanisms, including antigen internalization via crosslinking, disruption of protein-protein interactions, and direct receptor blocking. Moreover, patient-derived mAbs enabled, for the first time, the structural determination of antibody-antigen interactions at the atomic level using cryogenic electron microscopy. Besides these already successful applications, mAbs are currently being used to investigate the immunological tolerance dysfunctions underlying diverse forms of AE, identify novel antigenic targets, and develop antigen-specific immunotherapies. Therefore, human mAbs not only enable an unprecedented in-depth characterization of autoantibody effects but also serve as critical scientific tools to address basic immunological questions, perform atomic-level structural analyses, and develop targeted therapies.

Autoantibodies against synaptic proteins have been associated with a wide range of neurological and psychiatric manifestations ranging from autoimmune encephalitis (AE) to seizures to dementia. However, antibody detection per se is not sufficient to establish pathogenicity. Indeed, direct and indirect evidence of pathogenicity requires reproducing the disease in a recipient through direct transfer of the antibodies (passive transfer) or active immunization. Several in vitro and in vivo studies support the pathogenic relevance of antibodies to synaptic proteins, although proof of pathogenicity is still pending for some of them. Synaptic antibodies have been shown to induce neuronal dysfunction through different mechanisms, including: 1) crosslinking and subsequent internalization with consequent reduction of receptor density (e.g. NMDAR antibodies); 2) blocking of the ligand binding site (e.g. GABABR antibodies); 3) disruption of protein-protein interaction (e.g. LGI1 antibodies); 4) complement activation and inflammation (e.g. AQP4 antibodies). Understanding these mechanisms has been relevant in supporting the use of immunotherapy in patients with neuronal surface antibody-related AE and has driven the development of tailored treatment. For instance, the demonstration of complement activation by AQP4 antibodies in neuromyelitis optica disorders has provided the rationale for using complement inhibitors in this disease. Nevertheless, despite the current advancement, numerous gaps in our knowledge of the specific mechanisms of each antibody remain, and newer disease models are needed. Filling these gaps is fundamental for developing novel and individualized treatment options in the future.