RT Journal Article
SR Electronic
T1 Therapeutic Cleavage of Anti–Aquaporin-4 Autoantibody in Neuromyelitis Optica by an IgG-Selective Proteinase
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1268
OP 1275
DO 10.1124/mol.113.086470
VO 83
IS 6
A1 Tradtrantip, Lukmanee
A1 Asavapanumas, Nithi
A1 Verkman, A. S.
YR 2013
UL http://molpharm.aspetjournals.org/content/83/6/1268.abstract
AB 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.