title: Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis.
abstract: Pulmonary alveolar proteinosis (PAP) is a severe autoimmune disease caused by autoantibodies that neutralize GM-CSF resulting in impaired function of alveolar macrophages. In this study, we characterize 21 GM-CSF autoantibodies from PAP patients and find that somatic mutations critically determine their specificity for the self-antigen. Individual antibodies only partially neutralize GM-CSF activity using an in vitro bioassay, depending on the experimental conditions, while, when injected in mice together with human GM-CSF, they lead to the accumulation of a large pool of circulating GM-CSF that remains partially bioavailable. In contrast, a combination of three non-cross-competing antibodies completely neutralizes GM-CSF activity in vitro by sequestering the cytokine in high-molecular-weight complexes, and in vivo promotes the rapid degradation of GM-CSF-containing immune complexes in an Fc-dependent manner. Taken together, these findings provide a plausible explanation for the severe phenotype of PAP patients and for the safety of treatments based on single anti-GM-CSF monoclonal antibodies.
authors.affiliation: 1] Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland [2] Institute of Microbiology, Eidgenössische Technische Hochschule (ETH), Zürich 8093, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Piccoli
authors.affiliation: Respiratory Disease Unit, IRCCS San Matteo Hospital Foundation, Pavia 27100, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Campo
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Chiara Silacci
authors.initials: CS
authors.lastname: Fregni
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Blanca Maria Fernandez
authors.initials: BM
authors.lastname: Rodriguez
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Minola
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.affiliation: Respiratory Disease Unit, IRCCS San Matteo Hospital Foundation, Pavia 27100, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Luisetti
authors.affiliation: 1] Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland [2] Humabs Biomed SA, Bellinzona 6500, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.affiliation: 1] Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland [2] Institute of Microbiology, Eidgenössische Technische Hochschule (ETH), Zürich 8093, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000235:genetics; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011649:Pulmonary Alveolar Proteinosis / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D000939:Epitopes; D017452:Receptors, IgG; D016178:Granulocyte-Macrophage Colony-Stimulating Factor