title: Evidence against cellular internalization in vivo of NMO-IgG, aquaporin-4, and excitatory amino acid transporter 2 in neuromyelitis optica.
abstract: Autoantibodies against astrocyte water channel aquaporin-4 (AQP4) are thought to be pathogenic in neuromyelitis optica (NMO). Prior work has suggested that a key component of NMO autoantibody (NMO-IgG) pathogenesis is internalization of AQP4 and the associated glutamate transporter EAAT2, leading to glutamate excitotoxicity. Here, we show selective endocytosis of NMO-IgG and AQP4 in transfected cell cultures, but little internalization in brain in vivo. AQP4-dependent endocytosis of NMO-IgG occurred rapidly in various AQP4-transfected cell lines, with efficient transport from early endosomes to lysosomes. Cell surface AQP4 was also reduced following NMO-IgG exposure. However, little or no internalization of NMO-IgG, AQP4, or EAAT2 was found in primary astrocyte cultures, nor was glutamate uptake affected by NMO-IgG exposure. Following injection of NMO-IgG into mouse brain, NMO-IgG binding and AQP4 expression showed a perivascular astrocyte distribution, without detectable cellular internalization over 24 h. We conclude that astrocyte endocytosis of NMO-IgG, AQP4, and EAAT2 is not a significant consequence of AQP4 autoantibody in vivo, challenging generally accepted views about NMO pathogenesis.
authors: Department of Medicine and Physiology, University of California, San Francisco, California 94143, USA.
authors: Julien
authors: J
authors: Ratelade
authors: Jeffrey L
authors: JL
authors: Bennett
authors: A S
authors: AS
authors: Verkman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051401:Aquaporin 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001323:Autoantibodies / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009471:Neuromyelitis Optica / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D013997:Time Factors
chemical_list: C496030:AQP4 protein, human; D000911:Antibodies, Monoclonal; C496031:Aqp4 protein, mouse; C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D001323:Autoantibodies; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human; C493396:Slc1a2 protein, mouse; C493395:Slc1a2 protein, rat