Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss
- 22 April 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica
- Vol. 123 (6), 861-872
- https://doi.org/10.1007/s00401-012-0986-4
Abstract
The pathogenesis of neuromyelitis optica (NMO) involves targeting of NMO-immunoglobulin G (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system. Prior work provided evidence for complement-dependent cytotoxicity (CDC) in NMO lesion development. Here, we show that antibody-dependent cellular cytotoxicity (ADCC), in the absence of complement, can also produce NMO-like lesions. Antibody-dependent cellular cytotoxicity was produced in vitro by incubation of mouse astrocyte cultures with human recombinant monoclonal NMO-IgG and human natural killer cells (NK-cells). Injection of NMO-IgG and NK-cells in mouse brain caused loss of AQP4 and GFAP, two characteristic features of NMO lesions, but little myelin loss. Lesions were minimal or absent following injection of: (1) control (non-NMO) IgG with NK-cells; (2) NMO-IgG and NK-cells in AQP4-deficient mice; or (3) NMO-IgG and NK-cells in wild-type mice together with an excess of mutated NMO-IgG lacking ADCC effector function. NK-cells greatly exacerbated NMO lesions produced by NMO-IgG and complement in an ex vivo spinal cord slice model of NMO, causing marked myelin loss. NMO-IgG can thus produce astrocyte injury by ADCC in a complement-independent and dependent manner, suggesting the potential involvement of ADCC in NMO pathogenesis.Keywords
This publication has 48 references indexed in Scilit:
- Complement-dependent Cytotoxicity in Neuromyelitis Optica Requires Aquaporin-4 Protein Assembly in Orthogonal ArraysPublished by Elsevier BV ,2012
- Neutrophil protease inhibition reduces neuromyelitis optica–immunoglobulin G–induced damage in mouse brainAnnals of Neurology, 2011
- Evidence against Cellular Internalization in Vivo of NMO-IgG, Aquaporin-4, and Excitatory Amino Acid Transporter 2 in Neuromyelitis OpticaPublished by Elsevier BV ,2011
- Anti–Aquaporin‐4 monoclonal antibody blocker therapy for neuromyelitis opticaAnnals of Neurology, 2011
- Ex vivo spinal cord slice model of neuromyelitis optica reveals novel immunopathogenic mechanismsAnnals of Neurology, 2011
- Aquaporin-4: orthogonal array assembly, CNS functions, and role in neuromyelitis opticaActa Pharmacologica Sinica, 2011
- Complement in neuroprotection and neurodegenerationTrends in Molecular Medicine, 2010
- Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in miceBrain, 2010
- Intrathecal pathogenic anti–aquaporin‐4 antibodies in early neuromyelitis opticaAnnals of Neurology, 2009
- Losing your nerves? Maybe it's the antibodiesNature Reviews Immunology, 2009