title: Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica.
abstract: Neuromyelitis optica (NMO) pathogenesis involves binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) present in serum to AQP4 on astrocytes, which causes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Human immunoglobulin G (hIgG) is effective for treatment of humorally mediated neurological autoimmune diseases and has been reported to improve disease outcome in a limited number of NMO patients. Here, we investigated hIgG actions on NMO-IgG pathogenicity using an in vivo rat model of NMO and in vitro assays. In rats administered NMO-IgG by intracerebral injection, the size of neuroinflammatory demyelinating lesions was reduced by ~50% when hIgG was administered by intraperitoneal injection to reach levels of 10-25mg/mL in rat serum, comparable with human therapeutic levels. In vitro, hIgG at 10mg/mL reduced by 90% NMO-IgG-mediated CDC following addition of NMO-IgG and human complement to AQP4-expressing cells. The hIgG effect was mainly on the classical complement pathway. hIgG at 10mg/mL also reduced by up to 90% NMO-IgG-mediated ADCC as assayed with human natural killer cells as effector cells. However, hIgG at up to 40mg/mL did not affect AQP4 cell surface expression or its supramolecular assembly in orthogonal arrays of particles, nor did it affect NMO-IgG binding to AQP4. We conclude that hIgG reduces NMO-IgG pathogenicity by inhibition of CDC and ADCC, providing a mechanistic basis to support further clinical evaluation of its therapeutic efficacy in NMO.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA; Department of Physiology, University of California, San Francisco, CA, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Ratelade
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA; Department of Physiology, University of California, San Francisco, CA, USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA; Department of Physiology, University of California, San Francisco, CA, USA. Electronic address: Alan.Verkman@ucsf.edu.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology* / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism*; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D009471:Neuromyelitis Optica / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G
keywords: AQP4; Astrocyte; Complement; Human immunoglobulin; NMO; Neuroinflammation