ArticleThe Journal of biological chemistry2012
Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 protein assembly in orthogonal arrays.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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Who cites it
83 citing papers in PubMed, 148 citations in OpenAlex.
- Dynamic characterization of pathological and functional deterioration in a mouse model of optic neuritis related to neuromyelitis optica spectrum disorder.Neural regeneration research · 2026Article
- Inflammatory transcriptomic signatures in a human cellular NMOSD model reveal upregulation of NF-κB and IL6 pathways.Scientific reports · 2025Article
- Induction of immune tolerance in NMOSD and MOGAD.Therapeutic advances in neurological disorders · 2025Review
- 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
- Modelling MOG antibody-associated disorder and neuromyelitis optica spectrum disorder in animal models: Spinal cord manifestations.Multiple sclerosis and related disorders · 2023Article
- Dissection of complement and Fc-receptor-mediated pathomechanisms of autoantibodies to myelin oligodendrocyte glycoprotein.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- T follicular helper cells contribute to pathophysiology in a model of neuromyelitis optica spectrum disorders.JCI insight · 2023Article
- ACT001 Relieves NMOSD Symptoms by Reducing Astrocyte Damage with an Autoimmune Antibody.Molecules (Basel, Switzerland) · 2023Article
- Pathology of myelin oligodendrocyte glycoprotein antibody-associated disease: a comparison with multiple sclerosis and aquaporin 4 antibody-positive neuromyelitis optica spectrum disorders.Frontiers in neurology · 2023Review
- Aquaporins in Nervous System.Advances in experimental medicine and biology · 2023Article
- Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.Acta neuropathologica · 2022Article
- A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations.Journal of neuroinflammation · 2022Article
- Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives.International journal of molecular sciences · 2022Review
- Aquaporin-4 in Neuromyelitis Optica Spectrum Disorders: A Target of Autoimmunity in the Central Nervous System.Biomolecules · 2022Review
- Microbial dysbiosis in the gut drives systemic autoimmune diseases.Frontiers in immunology · 2022Review
- Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders.Frontiers in immunology · 2022Article
- Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder.Scientific reports · 2021Article
- Neuromyelitis optica (NMO)-IgG-driven organelle reorganization in human iPSC-derived astrocytes.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies.Journal of neuroinflammation · 2021Review
- Treatment of Neuromyelitis Optica Spectrum Disorders.International journal of molecular sciences · 2021Review
23 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system in which binding of pathogenic autoantibodies (NMO-IgG) to astrocyte aquaporin-4 (AQP4) causes complement-dependent cytotoxicity (CDC) and inflammation. We previously reported a wide range of binding affinities of NMO-IgGs to AQP4 in separate tetramers versus intramembrane aggregates (orthogonal arrays of particles, OAPs). We report here a second, independent mechanism by which CDC is affected by AQP4 assembly. Utilizing lactate dehydrogenase release and live/dead cell cytotoxicity assays, we found in different cell lines, and with different monoclonal and patient-derived NMO-IgGs, that CDC was greatly (>100-fold) reduced in cells expressing M1- versus M23-AQP4. Studies using a M23-AQP4 mutant containing an OAP-disrupting mutation, and in cells expressing AQP4 in different M1/M23 ratios, indicated that NMO-IgG-dependent CDC requires AQP4 OAP assembly. In contrast, antibody-dependent cell-mediated cytotoxicity produced by natural killer cells did not depend on AQP4 OAP assembly. Measurements of C1q binding and complement attack complex (C9neo) supported the conclusion that the greatly enhanced CDC by OAPs is due to efficient, multivalent binding of C1q to clustered NMO-IgG on OAPs. We conclude that AQP4 assembly in OAPs is required for CDC in NMO, establishing a new mechanism of OAP-dependent NMO pathogenesis. Disruption of AQP4 OAPs may greatly reduce NMO-IgG dependent CDC and NMO pathology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.