Mouse model of neuromyelitis optica spectrum disorders with aquaporin-4 autoimmunity and spinal cord pathologies

Abstract

Objective: To establish a mouse model of neuromyelitis optica spectrum disorders (NMOSD) with aquaporin-4 (AQP4) autoimmunity seropositive for immunoglobulin G (IgG) AQP4 autoantibodies. Methods: We performed DNA immunisation in wild-type mice with plasmid encoding mouse AQP4 M23 isoform via in vivo electroporation of skeletal muscle. Results: DNA immunisation–induced inflammation and increased expression of AQP4 in muscle membrane in a punctuate distribution were suggestive of high-order orthogonal array of particles. Immunoglobulin G AQP4 autoantibodies were detected by cell-based assay in peripheral blood of mice immunised with AQP4 gene and pretreatment with CFA and PTx, but not in control mice. Immunoglobulin G AQP4 autoantibodies infiltrated into the spinal cord through a disrupted blood-brain barrier. Mice seropositive for IgG AQP4 autoantibodies had spinal cord pathologies including loss of AQP4 and glial fibrillary acidic protein, deposition of complement activation products (C5b-9), infiltration of macrophages, neutrophils and eosinophils, activation of microglia/ macrophages, increased proinflammatory cytokines (tumour necrosis factor α, interleukin 1β and interleukin 6) levels, demyelination and loss of oligodendrocytes and axons. Importantly, these spinal cord pathologies in mice with IgG AQP4 autoantibodies were associated with motor impairment. Conclusions: We developed a mouse model of NMOSD with circulating IgG AQP4 autoantibodies and NMOSDlike spinal cord pathologies. This model is useful for studying pathogenesis and novel therapeutics in NMOSD. Acknowledgement: This study was supported by Seed Fund for Basic Research, The University of Hong Kong, Hong Kong (Ref 201811159182).