Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies.
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.
Nicchia
Grazia Paola
GP
Department of General and Environmental Physiology and Centre of Excellence in Comparative Genomics (CEGBA), University of Bari, Bari, Italy.
Mastrototaro
Mauro
M
Rossi
Andrea
A
Pisani
Francesco
F
Tortorella
Carla
C
Ruggieri
Maddalena
M
Lia
Anna
A
Trojano
Maria
M
Frigeri
Antonio
A
Svelto
Maria
M
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
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