title: Therapeutic cleavage of anti-aquaporin-4 autoantibody in neuromyelitis optica by an IgG-selective proteinase.
abstract: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system caused by binding of pathogenic IgG autoantibodies (NMO-IgG) to astrocyte water channel aquaporin-4 (AQP4). Astrocyte damage and downstream inflammation require NMO-IgG effector function to initiate complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we evaluated the potential therapeutic utility of the bacterial enzyme IdeS (IgG-degrading enzyme of Streptococcus pyogenes), which selectively cleaves IgG antibodies to yield Fc and F(ab')(2) fragments. In AQP4-expressing cell cultures, IdeS treatment of monoclonal NMO-IgGs and NMO patient sera abolished CDC and ADCC, even when IdeS was added after NMO-IgG was bound to AQP4. Binding of NMO-IgG to AQP4 was similar to that of the NMO-F(ab')(2) generated by IdeS cleavage. NMO-F(ab')(2) competitively displaced pathogenic NMO-IgG, preventing cytotoxicity, and the Fc fragments generated by IdeS cleavage reduced CDC and ADCC. IdeS efficiently cleaved NMO-IgG in mice in vivo, and greatly reduced NMO lesions in mice administered NMO-IgG and human complement. IgG-selective cleavage by IdeS thus neutralizes NMO-IgG pathogenicity, and yields therapeutic F(ab')(2) and Fc fragments. IdeS treatment, by therapeutic apheresis or direct administration, may be beneficial in NMO.
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA, USA.
authors.forename: Lukmanee
authors.initials: L
authors.lastname: Tradtrantip
authors.forename: Nithi
authors.initials: N
authors.lastname: Asavapanumas
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D051401:Aquaporin 4 / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism*; D001426:Bacterial Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D003165:Complement System Proteins / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D003546:Cysteine Endopeptidases / Q000494:pharmacology* / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009471:Neuromyelitis Optica / Q000276:immunology* / Q000473:pathology / Q000628:therapy
chemical_list: D051401:Aquaporin 4; D001323:Autoantibodies; D001426:Bacterial Proteins; D007074:Immunoglobulin G; C442815:Mac-1-like protein, Streptococcus; D003165:Complement System Proteins; D003546:Cysteine Endopeptidases