Work

AQP4 antibody-induced astrocyte injury reshapes CNS immune architecture in a combined EAE–AQP4-IgG model of neuromyelitis optica spectrum disorder

Year: 2026

Type: article

Abstract: Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory autoimmune diseases of the central nervous system (CNS) that share demyelinating features but differ fundamentally in pathogenesis. The discovery of neuromyelitis optica immunoglobulin G antibodies (NMO-IgG) that target aquaporin-4 (AQP4) established NMOSD as a distinct clinical entity, although the experimental platforms used to dissect the mechanistic basis of this disorder remain insufficiently defined. Thus, this study aimed to develop a combined EAE-AQP4-IgG model by intrathecally delivering patient-derived NMO-IgG and human complement into pre-immunized mice to compare the associated pathology with that of experimental autoimmune encephalomyelitis (EAE), a representative model of MS. Both models exhibited blood–brain barrier (BBB) disruption, reflected by altered ZO-1 and CD31 expression. Notably, glial fibrillary acidic protein (GFAP) was strongly upregulated in EAE, whereas in the combined EAE-AQP4-IgG model, GFAP was acutely lost, indicating antibody-mediated astrocyte destruction. Consistently, AQP4 expression was markedly reduced in combined EAE-AQP4-IgG model animals. Combined EAE-AQP4-IgG model mice also displayed more severe demyelination and inflammation, confirmed by Luxol Fast Blue and H&E staining, electron microscopy, and MBP/Iba1 immunostaining. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) further revealed distinct inflammatory signatures: CCL2 and BCL6 were elevated in EAE, whereas IL-6 , IL-17A , CXCL13 , and PRDM1 were strongly upregulated in combined EAE-AQP4-IgG model. These differences were consistently observed across the brain, spinal cord, and optic nerve, albeit with regional variation. These results suggest that AQP4-IgG-induced astrocyte injury may redirect the CNS-related inflammatory milieu, shifting the CCL2-dominant, repair-permissive EAE environment into an IL-6–CXCL13–PRDM1 axis-driven, B cell-amplifying, remyelination-inefficient state that closely resembles the immunopathological context of human NMOSD. This combined EAE-AQP4-IgG model provides a robust platform for mechanistic investigation and therapeutic development.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1899823