title: Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss.
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.
authors.affiliation: Department of Medicine, University of California, San Francisco, 1246 Health Sciences East Tower, San Francisco, CA 94143-0521, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Ratelade
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Samira
authors.initials: S
authors.lastname: Saadoun
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.forename: Marios C
authors.initials: MC
authors.lastname: Papadopoulos
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity; D051401:Aquaporin 4 / Q000172:deficiency / Q000378:metabolism*; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009471:Neuromyelitis Optica / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D007074:Immunoglobulin G; D003165:Complement System Proteins