Neuro-immunobiology and treatment assessment in a mouse model of anti-NMDAR encephalitis

作者：Estibaliz Maudes, Jesús Planagumà, Laura Marmolejo, Marija Radosevic, Ana Beatriz Serafim, Esther Aguilar, Carlos Sindreu, Jon Landa, Anna García‐Serra, Francesco Mannara, Marina Cunquero, Anna M. Smith, Chiara Milano, Paula Peixoto-Moledo, Mar Guasp, Raquel Ruiz‐García, Sarah M. Gray, Marianna Spatola, Pablo Loza‐Álvarez, Lídia Sabater, Carlos Matute, Josep Dalmau · 发表于：Brain · 年份：2024 · DOI：10.1093/brain/awae410 · 被引用次数：33 · 研究领域：Autoimmune Neurological Disorders and Treatments、Neuroscience and Neuropharmacology Research、Genetics and Neurodevelopmental Disorders

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a disorder mediated by autoantibodies against the GluN1 subunit of NMDAR. It occurs with severe neuropsychiatric symptoms that often improve with immunotherapy. Clinical studies and animal models based on patients' antibody transfer or NMDAR immunization suggest that the autoantibodies play a major pathogenic role. Yet, there is an important need for models offering an all-inclusive neuro-immunobiology of the disease together with a clinical course long enough to facilitate the assessment of potential new treatments. To develop such a model, eight-week-old female mice (C57BL/6J) were immunized (Days 1 and 28) with GluN1356-385 peptide or saline with AddaVaxTM adjuvant and pertussis toxin. After developing behavioural alterations (∼Day 35), subsets of mice were treated with an anti-CD20 (Day 35), a positive allosteric modulator (PAM) of NMDAR (PAM-NMDAR, SGE-301) from Days 45 to 71, or both. GluN1-antibody synthesis, epitope spreading, effects of antibodies on density and function of NMDAR, brain immunological infiltrates, microglial activation and NMDAR phagocytosis, and antibody synthesis in cultured inguinal and deep cervical lymph nodes were assessed with techniques including immunohistochemistry, calcium imaging, confocal and super-resolution microscopy, electrophysiology and flow cytometry. Changes in memory and behaviour were assessed with a panel of behavioural tests and clinical/subclinical seizures with brain...