PubMed:23571414 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/23571414","sourcedb":"PubMed","sourceid":"23571414","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/23571414","text":"Therapeutic cleavage of anti-aquaporin-4 autoantibody in neuromyelitis optica by an IgG-selective proteinase.\nNeuromyelitis 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.","tracks":[{"project":"Allie","denotations":[{"id":"SS1_23571414_1_0","span":{"begin":110,"end":130},"obj":"expanded"},{"id":"SS2_23571414_1_0","span":{"begin":132,"end":135},"obj":"abbr"},{"id":"SS1_23571414_1_1","span":{"begin":193,"end":258},"obj":"expanded"},{"id":"SS2_23571414_1_1","span":{"begin":260,"end":267},"obj":"abbr"},{"id":"SS1_23571414_1_2","span":{"begin":296,"end":307},"obj":"expanded"},{"id":"SS2_23571414_1_2","span":{"begin":309,"end":313},"obj":"abbr"},{"id":"SS1_23571414_2_0","span":{"begin":407,"end":440},"obj":"expanded"},{"id":"SS2_23571414_2_0","span":{"begin":442,"end":445},"obj":"abbr"},{"id":"SS1_23571414_2_1","span":{"begin":451,"end":496},"obj":"expanded"},{"id":"SS2_23571414_2_1","span":{"begin":498,"end":502},"obj":"abbr"}],"relations":[{"id":"AE1_23571414_1_0","pred":"abbreviatedTo","subj":"SS1_23571414_1_0","obj":"SS2_23571414_1_0"},{"id":"AE1_23571414_1_1","pred":"abbreviatedTo","subj":"SS1_23571414_1_1","obj":"SS2_23571414_1_1"},{"id":"AE1_23571414_1_2","pred":"abbreviatedTo","subj":"SS1_23571414_1_2","obj":"SS2_23571414_1_2"},{"id":"AE1_23571414_2_0","pred":"abbreviatedTo","subj":"SS1_23571414_2_0","obj":"SS2_23571414_2_0"},{"id":"AE1_23571414_2_1","pred":"abbreviatedTo","subj":"SS1_23571414_2_1","obj":"SS2_23571414_2_1"}],"attributes":[{"subj":"SS1_23571414_1_0","pred":"source","obj":"Allie"},{"subj":"SS2_23571414_1_0","pred":"source","obj":"Allie"},{"subj":"SS1_23571414_1_1","pred":"source","obj":"Allie"},{"subj":"SS2_23571414_1_1","pred":"source","obj":"Allie"},{"subj":"SS1_23571414_1_2","pred":"source","obj":"Allie"},{"subj":"SS2_23571414_1_2","pred":"source","obj":"Allie"},{"subj":"SS1_23571414_2_0","pred":"source","obj":"Allie"},{"subj":"SS2_23571414_2_0","pred":"source","obj":"Allie"},{"subj":"SS1_23571414_2_1","pred":"source","obj":"Allie"},{"subj":"SS2_23571414_2_1","pred":"source","obj":"Allie"}]},{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":156,"end":169},"obj":"HP_0011096"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubmedHPO"}]},{"project":"Inflammaging","denotations":[{"id":"T1","span":{"begin":0,"end":109},"obj":"Sentence"},{"id":"T2","span":{"begin":110,"end":315},"obj":"Sentence"},{"id":"T3","span":{"begin":316,"end":504},"obj":"Sentence"},{"id":"T4","span":{"begin":505,"end":714},"obj":"Sentence"},{"id":"T5","span":{"begin":715,"end":889},"obj":"Sentence"},{"id":"T6","span":{"begin":890,"end":985},"obj":"Sentence"},{"id":"T7","span":{"begin":986,"end":1138},"obj":"Sentence"},{"id":"T8","span":{"begin":1139,"end":1271},"obj":"Sentence"},{"id":"T9","span":{"begin":1272,"end":1393},"obj":"Sentence"},{"id":"T10","span":{"begin":1394,"end":1486},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":109},"obj":"Sentence"},{"id":"T2","span":{"begin":110,"end":315},"obj":"Sentence"},{"id":"T3","span":{"begin":316,"end":504},"obj":"Sentence"},{"id":"T4","span":{"begin":505,"end":714},"obj":"Sentence"},{"id":"T5","span":{"begin":715,"end":889},"obj":"Sentence"},{"id":"T6","span":{"begin":890,"end":985},"obj":"Sentence"},{"id":"T7","span":{"begin":986,"end":1138},"obj":"Sentence"},{"id":"T8","span":{"begin":1139,"end":1271},"obj":"Sentence"},{"id":"T9","span":{"begin":1272,"end":1393},"obj":"Sentence"},{"id":"T10","span":{"begin":1394,"end":1486},"obj":"Sentence"}],"attributes":[{"subj":"T1","pred":"source","obj":"Inflammaging"},{"subj":"T2","pred":"source","obj":"Inflammaging"},{"subj":"T3","pred":"source","obj":"Inflammaging"},{"subj":"T4","pred":"source","obj":"Inflammaging"},{"subj":"T5","pred":"source","obj":"Inflammaging"},{"subj":"T6","pred":"source","obj":"Inflammaging"},{"subj":"T7","pred":"source","obj":"Inflammaging"},{"subj":"T8","pred":"source","obj":"Inflammaging"},{"subj":"T9","pred":"source","obj":"Inflammaging"},{"subj":"T10","pred":"source","obj":"Inflammaging"},{"subj":"T1","pred":"source","obj":"Inflammaging"},{"subj":"T2","pred":"source","obj":"Inflammaging"},{"subj":"T3","pred":"source","obj":"Inflammaging"},{"subj":"T4","pred":"source","obj":"Inflammaging"},{"subj":"T5","pred":"source","obj":"Inflammaging"},{"subj":"T6","pred":"source","obj":"Inflammaging"},{"subj":"T7","pred":"source","obj":"Inflammaging"},{"subj":"T8","pred":"source","obj":"Inflammaging"},{"subj":"T9","pred":"source","obj":"Inflammaging"},{"subj":"T10","pred":"source","obj":"Inflammaging"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"Allie","color":"#b793ec","default":true},{"id":"PubmedHPO","color":"#93ec9d"},{"id":"Inflammaging","color":"#ec93a2"}]}]}}