title: Pathways Responsible for Human Autoantibody and Therapeutic Intravenous IgG Activity in Humanized Mice.
abstract: Immunoglobulin G (IgG) antibodies are major drivers of autoimmune pathology, but they are also used in the form of intravenous IgG (IVIg) therapy to suppress autoantibody activity. To identify the pathways underlying human autoantibody and IVIg activity, we established a humanized mouse model of an autoantibody-dependent autoimmune disease responding to treatment with IVIg preparations. We show that the human IgG subclass strongly impacts autoantibody activity and that the Fc-receptor genotype of the human donor immune system further modulates autoantibody activity. Human mononuclear phagocytes were responsible for autoantibody activity, and IVIg therapy was able to suppress disease pathology in an Fc-fragment-dependent manner. While highly sialylated IgG glycovariants were essential for IVIg activity, it was independent of the Fc-receptor genotype and did not result in a general block of activating or the neonatal Fc-receptor. These findings may help in the development of strategies to block autoantibody and enhance therapeutic IVIg activity in humans.
authors.affiliation: Institute of Genetics at the Department of Biology, Friedrich Alexander University Erlangen-Nürnberg, Erwin-Rommel-Straβe 3, 91058 Erlangen, Germany.
authors.forename: Inessa
authors.initials: I
authors.lastname: Schwab
authors.affiliation: Institute of Genetics at the Department of Biology, Friedrich Alexander University Erlangen-Nürnberg, Erwin-Rommel-Straβe 3, 91058 Erlangen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Lux
authors.affiliation: Institute of Genetics at the Department of Biology, Friedrich Alexander University Erlangen-Nürnberg, Erwin-Rommel-Straβe 3, 91058 Erlangen, Germany. Electronic address: falk.nimmerjahn@fau.de.
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology*; D001323:Autoantibodies / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000276:immunology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G