Abstract: Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory autoimmune diseases of the central nervous system (CNS) characterized by demyelination, leading to neurological dysfunction. Due to their overlapping clinical manifestations and affected regions, MS and NMOSD were historically considered a single disease entity. However, the identification of anti-aquaporin-4 (AQP4) antibodies (NMO-IgG) in the serum of NMOSD patients has established NMOSD as a distinct disease. Despite ongoing efforts to differentiate these diseases, their underlying pathogenic mechanisms remain elusive. Here, we established an NMOSD rodent model by intrathecally administering patient-derived NMO-IgG and human complement. Using this model, we performed comparative histological and molecular analyses with the experimental autoimmune encephalomyelitis (EAE) model, a representative MS model. GFAP expression showed opposing patterns, with significant upregulation in EAE but acute loss in the NMOSD model, reflecting astrocyte gliosis and destruction, respectively. Similarly, AQP4 expression was markedly reduced in the NMOSD model compared to EAE, consistent with the pathogenic mechanism of AQP4 antibody-mediated astrocyte damage. Moreover, the NMOSD model exhibited more severe demyelination and inflammation, as demonstrated by Luxol Fast Blue (LFB) and H&E staining. These pathological differences were observed across the brain, spinal cord, and optic nerve, with regional variations in their manifestation. Our findings highlight distinct pathological differences between MS and NMOSD, underscoring the utility of our NMOSD model in advancing the understanding of NMOSD pathogenesis and facilitating therapeutic development.
Funding Source: It was supported by the Korean Fund for Regenerative Medicine grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Health & Welfare) (22C0628L1-11) and BK21 Four Institute of Precision Public Health.
