Reply to Rossi et al.: Immunohistopathological findings in neuromyelitis optica concur with immunobiological observations in vitro

Abstract

Aquaporin-4 (AQP4) water-channel–specific IgG unifies a spectrum of autoimmune astrocytopathies exemplified by neuromyelitis optica (NMO): relapsing inflammatory myelopathy, optic neuritis, and disorders affecting AQP4-rich circumventricular organs. AQP4-IgG detection in serum distinguishes these disorders from other inflammatory demyelinating disorders. The points of our study (1) were to emphasize that (i) IgG-AQP4 interaction has multiple molecular sequelae that plausibly account for diverse pathology (edema, inflammation, demyelination, and necrosis) and (ii) some outcomes are AQP4 isoform (M1 or M23)-specific. Our study involves immunocytochemistry and freeze-fracture EM of cultured rodent astrocytes, HEK293 cells transfected with non-tagged human AQP4s, Xenopus oocytes expressing GFP-tagged human AQP4s, and NMO patient brain immunohistopathology. Because serum IgG is polyclonal, we used high-titered sera (or IgG) pooled from at least 50 patients with NMO (binding > 1,000 nmol AQP4/L) to broadly investigate potentially pathogenic, AQP4-specific outcomes of IgG-AQP4 interaction in live cells. The correspondents question our data’s validity (2), citing conflicting data they obtained by using various AQP4 isoform-transfected cell types, sera from six individual patients with NMO, and mouse neuropathology.