ArticleActa neuropathologica communications2019
Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody-dependent cellular cytotoxicity.
Article in Acta neuropathologica communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 66 citations in OpenAlex.
- Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder.Journal of neurology, neurosurgery, and psychiatry · 2023Trial
- FPR2/ALX stimulation modulates microglia and natural killer cells to restrict autoimmune astrocytopathy.Acta pharmacologica Sinica · 2026Article
- miR-6836-5p Drives Astrocyte Pro-survival Signaling Through DLG2-Hippo-YAP Pathway Under AQP4-IgG + ve NMOSD Stress.Molecular neurobiology · 2026Article
- Dissecting NMOSD pathogenesis through animal models: a mechanism-oriented systems perspective.Frontiers in immunology · 2026Review
- Inflammatory transcriptomic signatures in a human cellular NMOSD model reveal upregulation of NF-κB and IL6 pathways.Scientific reports · 2025Article
- High-Efficacy Treatment in Neuromyelitis Optica Specturm Disorder Patients With Seropositive AQP4 Antibodies-A Real-World Study.Annals of clinical and translational neurology · 2025Article
- Complement inhibition rapidly blocks lesion extension and facilitates remyelination in neuromyelitis optica.Acta neuropathologica communications · 2025Article
- Complement activation in immunological neurological disorders: mechanisms and therapeutic strategies.Frontiers in neurology · 2025Review
- Clinical features and prognosis of NMOSD patients with positive autoimmune antibodies.Frontiers in neurology · 2025Article
- The Different Immune Response Between Onset and Remission of AQP4 Antibody-Positive Optic Neuritis Based on RNA Sequencing of Whole Blood.Journal of inflammation research · 2025Article
- Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder.International journal of molecular sciences · 2024Article
- Moving towards a new era for the treatment of neuromyelitis optica spectrum disorders.Journal of neurology · 2024Review
- Pathogenic myelin-specific antibodies in multiple sclerosis target conformational proteolipid protein 1-anchored membrane domains.The Journal of clinical investigation · 2023Article
- Modelling MOG antibody-associated disorder and neuromyelitis optica spectrum disorder in animal models: Spinal cord manifestations.Multiple sclerosis and related disorders · 2023Article
- MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity.JCI insight · 2023Article
- Anti-IgLON5 disease: a novel topic beyond neuroimmunology.Neural regeneration research · 2023Review
- The Pathological Activation of Microglia Is Modulated by Sexually Dimorphic Pathways.International journal of molecular sciences · 2023Review
- T follicular helper cells contribute to pathophysiology in a model of neuromyelitis optica spectrum disorders.JCI insight · 2023Article
- More Efficient Complement Activation by Anti-Aquaporin-4 Compared With Anti-Myelin Oligodendrocyte Glycoprotein Antibodies.Neurology(R) neuroimmunology & neuroinflammation · 2023Article
- Astrocyte polarization in glaucoma: a new opportunity.Neural regeneration research · 2022Review
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Cellular injury in AQP4-IgG seropositive neuromyelitis spectrum disorder (herein called NMO) involves AQP4-IgG binding to astrocytes, resulting in astrocyte injury by complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) mechanisms. The rapid disease progression, severe tissue damage, and abundant leukocyte infiltration seen in some NMO patients suggest a more direct mechanism for demyelination and neurologic deficit than secondary injury from astrocyte loss. Here, we report evidence for an 'ADCC bystander mechanism' in NMO involving injury to nearby cells by leukocytes following their activation by AQP4-bound AQP4-IgG on astrocytes. In model cocultures containing AQP4-expressing and null CHO cells, AQP4-IgG and complement killed bystander null cells to ~ 100 μm away from AQP4-expressing cells; AQP4-IgG and NK cells produced bystander killing to ~ 300 μm, with perforin deposition seen on injured null cells. Bystander cytotoxicity was also seen with neutrophil-mediated ADCC and in astrocyte-neuron cocultures. Mechanistic studies, including real-time imaging, suggested that leukocytes activated by an AQP4-dependent ADCC mechanism injure bystander cells by direct targeted exocytosis on neighboring cells and not by diffusion of soluble granule contents. In support of this conclusion, ADCC bystander injury was preferentially reduced by an RGDS peptide that inhibits integrin adhesion. Evidence for ADCC bystander injury to oligodendrocytes and neurons was also found in mice following intracerebral injection of AQP4-IgG and NK cells, which was inhibited by RGDS peptide. These results establish a novel cellular pathogenesis mechanism in AQP4-IgG seropositive NMO and provide evidence that inflammatory mechanisms can cause widespread tissue damage in NMO independently of the secondary effects from astrocyte loss.
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