title: Characterization of pathogenic human monoclonal autoantibodies against GM-CSF.
abstract: The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Wang
authors.forename: Christy A
authors.initials: CA
authors.lastname: Thomson
authors.forename: Lenka L
authors.initials: LL
authors.lastname: Allan
authors.forename: Linda M
authors.initials: LM
authors.lastname: Jackson
authors.forename: Melanie
authors.initials: M
authors.lastname: Olson
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hercus
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Nero
authors.forename: Amanda
authors.initials: A
authors.lastname: Turner
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Angel L
authors.initials: AL
authors.lastname: Lopez
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: John W
authors.initials: JW
authors.lastname: Schrader
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018604:Epitope Mapping / Q000379:methods; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009154:Mutation; D009504:Neutrophils / Q000378:metabolism; D017354:Point Mutation; D011649:Pulmonary Alveolar Proteinosis / Q000276:immunology* / Q000378:metabolism; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D039481:CD11b Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: autoantibody; autoimmune; biotherapeutic; cytokine; three-dimensional model