title: Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies.
abstract: Neuromyelitis optica (NMO) is an inflammatory autoimmune demyelinating disease of the central nervous system (CNS) which in autoantibodies produced by patients with NMO (NMO-IgG) recognize a glial water channel protein, Aquaporin-4 (AQP4) expressed as two major isoforms, M1- and M23-AQP4, in which the plasma membrane form orthogonal arrays of particles (OAPs). AQP4-M23 is the OAP-forming isoform, whereas AQP4-M1 alone is unable to form OAPs. The function of AQP4 organization into OAPs in normal physiology is unknown; however, alteration in OAP assemblies is reported for several CNS pathological states. In this study, we demonstrate that in the CNS, NMO-IgG is able to pull down both M1- and M23-AQP4 but experiments performed using cells selectively transfected with M1- or M23-AQP4 and native tissues show NMO-IgG epitope to be intrinsic in AQP4 assemblies into OAPs. Other OAP-forming water-channel proteins, such as the lens Aquaporin-0 and the insect Aquaporin-cic, were not recognized by NMO-IgG, indicating an epitope characteristic of AQP4-OAPs. Finally, water transport measurements show that NMO-IgG treatment does not significantly affect AQP4 function. In conclusion, our results suggest for the first time that OAP assemblies are required for NMO-IgG to recognize AQP4.
authors.affiliation: Department of General and Environmental Physiology and Centre of Excellence in Comparative Genomics (CEGBA), University of Bari, Bari, Italy.
authors.forename: Grazia Paola
authors.initials: GP
authors.lastname: Nicchia
authors.forename: Mauro
authors.initials: M
authors.lastname: Mastrototaro
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
authors.forename: Carla
authors.initials: C
authors.lastname: Tortorella
authors.forename: Maddalena
authors.initials: M
authors.lastname: Ruggieri
authors.forename: Anna
authors.initials: A
authors.lastname: Lia
authors.forename: Maria
authors.initials: M
authors.lastname: Trojano
authors.forename: Antonio
authors.initials: A
authors.lastname: Frigeri
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D020346:Aquaporins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005136:Eye Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D006430:Hemiptera; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D019476:Insect Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009471:Neuromyelitis Optica / Q000276:immunology* / Q000378:metabolism; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: C102524:AQPcic protein, Cicadella viridis; C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D020346:Aquaporins; D001323:Autoantibodies; D005136:Eye Proteins; D007074:Immunoglobulin G; D019476:Insect Proteins; D020033:Protein Isoforms; C030328:aquaporin 0