title: Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications.
abstract: Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen-autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF-GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.
authors: Department of Lead Identification and Optimization Support, Structural Research Group, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach, Germany. michaela.blech@boehringer-ingelheim.com
authors: Michaela
authors: M
authors: Blech
authors: Daniel
authors: D
authors: Seeliger
authors: Barbara
authors: B
authors: Kistler
authors: Margit M T
authors: MM
authors: Bauer
authors: Mathias
authors: M
authors: Hafner
authors: Stefan
authors: S
authors: Hörer
authors: Markus
authors: M
authors: Zeeb
authors: Herbert
authors: H
authors: Nar
authors: John E
authors: JE
authors: Park
mesh_terms: D000936:Antigen-Antibody Complex / Q000737:chemistry; D001323:Autoantibodies / Q000737:chemistry* / Q000276:immunology* / Q000627:therapeutic use; D001666:Binding Sites, Antibody / Q000187:drug effects; D003460:Crystallization; D018604:Epitope Mapping; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry*; D008958:Models, Molecular; D011649:Pulmonary Alveolar Proteinosis / Q000276:immunology*
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D016178:Granulocyte-Macrophage Colony-Stimulating Factor