CHARACTERIZATION OF BRAIN INNATE IMMUNE INFILTRATES, ANTIBODY DYNAMICS AND FUNCTIONALITIES IN A MOUSE MODEL OF ANTI-NMDAR ENCEPHALITIS

Anti-NMDA receptor encephalitis (NMDARe) is a neuroinflammatory disease mediated by pathogenic autoantibodies against the GluN1 subunit of NMDAR, resulting in receptor crosslinking and internalization, neuronal dysfunction, and behavioral and memory impairments. The contribution of innate immune cells in antibody pathogenicity is unknown. We aimed to define antibody dynamics and innate immune mechanisms in a murine model of NMDARe (Maudes et al, Brain 2025). Female C57BL/6 mice were immunized with an NMDAR-peptide or saline. Flow cytometry was used to determine: 1) serum NMDAR-specific IgM, IgG and IgG subclasses (1, 2a, 2b, 3) (days 7-14-28-36-42 post-immunization); 2) binding to Fcγ receptors 1–4 (day 42); 3) antibody-mediated effector functions (phagocytosis by monocytes, neutrophils, microglia and complement activation) (day 42). Brain innate immune infiltrates (neutrophils, macrophages, NK cells), microglial activation, and complement deposition were assessed by confocal imaging (day 14 and 42). Starting from day 14, immunized mice, but not controls, developed serum NMDAR-specific IgM (which declined over time) and IgG (which remained elevated), mainly IgG1, with lower levels of IgG2b > IgG2a (but no IgG3). Antibodies showed enhanced capacity to bind FcγR2 and FcγR3 and to activate complement and phagocytosis by neutrophils, monocytes and microglia. On day 14, confocal microscopy revealed brain infiltration of neutrophils, macrophages, and NK cells, which persisted (neutrophil) or increased (NK cells) on day 42. Microglia activation and complement deposition will be reported. These findings support a role for antibody-mediated innate immune functions in the pathogenesis of NMDARe.