Innate Immune Responses and Antibody Dynamics in an Animal Model of Anti-NMDAR Encephalitis
Laura Marmolejo Alcaide1, Mariona Perez1, Afnaan AlSabbry1, Claudia Papi2, Chiara Milano3, Ana Beatriz Serafim1, Jesus Planagumà1, Esther Aguilar1, Lidia Sabater1, Estibaliz Maudes4, Josep Dalmau5, Marianna Spatola1
1Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain, 2Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; Catholic University of the Sacred Heart, Rome, Italy, 3Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; University of Pisa, Pisa, Italy, 4Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany, 5Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; Service of Neurology, University of Pennsylvania, Philadelphia, USA
Objective:
To characterize antibody class/subclass dynamics and innate immune responses in a mouse model of anti-NMDAR encephalitis that closely resembles the human disease (Maudes et al, Brain 2025).
Background:
Anti-NMDAR encephalitis is driven by pathogenic IgG1 autoantibodies that disrupt neuronal function and reproduce disease features in passive and active immunization models. While these models have elucidated adaptive immune mechanisms and uncovered microglial involvement, the temporal dynamics of antibody classes/subclasses and the role of innate immunity remain unexplored.
Design/Methods:
Female C57BL/6 mice were immunized with an NMDAR peptide or saline plus AddaVax and pertussis toxin. NMDAR-specific IgM, IgG, and IgG subclasses (1-4) were quantified in serial sera (days 7-14-28-36-42 post-immunization) by flow cytometry. At days 14 and 42, brain innate immune infiltrates (neutrophils, macrophages, NK cells), microglial activation, complement, and IgG deposition were analyzed by confocal imaging. Antibody-dependent effector functions (phagocytosis by monocytes, neutrophils or microglia, complement activation) and Fcγ receptors (FcγR 1–4) binding were assessed at day 42 using flow
cytometry.Results:
Immunized mice, but not controls, developed serum NMDAR-autoantibodies (IgM, IgG) by day 14. IgM peaked at day 14 and declined, whereas IgG remained elevated through day 42, predominantly IgG1 and IgG2b. At day 42, these antibodies enhanced monocyte- and microglia-mediated phagocytosis (and to a lesser extent also neutrophil) and complement activation. Confocal microscopy revealed increased brain infiltration of neutrophils, macrophages, and NK cells at both time points, with elevated hippocampal microglial activation and IgG deposition at day 42, but not day 14. FcγR-antibody binding and brain complement deposition will be reported.
Conclusions:
Innate immune cells infiltrate the brain early after immune activation, coinciding with the rise of NMDAR-IgG antibodies that strongly activate innate effector functions. These findings suggest that innate immunity plays an active role in disease pathogenesis in this model of anti-NMDAR encephalitis.
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