Animal models of autoimmune encephalitis

Abstract

Purpose of the review

To provide an overview of animal models and mechanisms of autoimmune encephalitides associated with autoantibodies against neuronal surface antigens.

Principal findings

Currently, 18 encephalitides are known to be mediated by cell-surface autoantibodies, with 16 targeting neuronal proteins or receptors. These diseases, which can affect patients of all ages, are severe but usually respond to immunotherapy. They also serve as valuable models for studying how immune disruptions of neuronal proteins impair memory, behavior, cognition, or lead to psychosis, seizures, or abnormal movements. The process of modeling these diseases involves three steps: (1) demonstrating that patients’ cerebrospinal fluid (CSF) or serum alters the structure or function of the target antigen; (2) confirming that animal transfer of patient-derived CSF, serum IgG, or monoclonal antibodies replicates the molecular effects and disease symptoms; and (3) developing active immunization-based animal models. While passive transfer models are crucial for demonstrating the pathogenicity of patients’ autoantibodies, they have limitations in fully elucidating the neuro-immunobiology of these diseases (e.g. contribution of T-cells, microglia, native immunity, deep cervical lymph nodes). Additionally, these models fall short in evaluating the long-term clinical course and immunological therapies. Active immunization models, currently available only for anti-NMDAR encephalitis, overcome these limitations, capturing the acute and chronic disease course, introducing novel neuroimmunological paradigms, and enabling the assessment of treatment strategies beyond initial immunotherapy.

Conclusions

Although animal models are inherently imperfect, current models of autoimmune encephalitides offer valuable neurobiological and immunological insights, facilitating the translation of experimental findings into clinical advancements.

Key points

• 1.
  Antibody-mediated encephalitides provide valuable models for studying how immune disruptions of neuronal proteins or receptors impair memory, behavior, cognition, or cause psychosis, seizures, or abnormal movements.
• 2.
  Modeling autoimmune encephalitides involves three steps: (1) assessing antibody effects on cultured neurons; (2) passively transferring human autoantibodies to animals to evaluate antigen-specific symptoms; and (3) inducing an autoimmune response in animals through immunization with full-length protein or peptide autoantigens.
• 3.
  Passive transfer models are essential for demonstrating autoantibody pathogenicity but are limited by a narrow symptom range, a short duration of effects, and the absence of other components of the immune response (e.g. inflammation, T-cells, microglia).
• 4.
  Active immunization models offer a comprehensive assessment of the neuro-immunobiology of these diseases, with a prolonged clinical course, enabling better evaluation of potential therapies.
• 5.
  A characterized model of anti-NMDAR encephalitis provides comprehensive insights into the disease’s neurobiology, presenting an immunological framework that emphasizes the role of microglia and deep cervical lymph nodes in driving polyclonal immune expansion.