caa a22 4500 528785834 20190713030955.0 cr unu---uuuuu 180924s2015 xx s 000 0 eng 10.3929/ethz-b-000102531 doi 10.1038/ncomms8375 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/102531 Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis [Elektronische Daten] [Luca Piccoli, Ilaria Campo, Chiara S. Fregni, Blanca M. Fernandez Rodriguez, Andrea Minola, Federica; id_orcid 0000-0003-3750-2752 Sallusto, Maurizio Luisetti, Davide Corti, Antonio Lanzavecchia] Nat Commun Open access ethresearch 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. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Piccoli Luca joint author Campo Ilaria joint author Fregni Chiara S. joint author Fernandez Rodriguez Blanca M. joint author Minola Andrea joint author Sallusto Federica; id_orcid 0000-0003-3750-2752 joint author Luisetti Maurizio joint author Corti Davide joint author Lanzavecchia Antonio joint author Nature Communications London : Nature Publishing Group 6, p. 7375 2041-1723 http://hdl.handle.net/20.500.11850/102531 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/102531 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Piccoli Luca joint author ETHRESEARCH 700 1- Campo Ilaria joint author ETHRESEARCH 700 1- Fregni Chiara S. joint author ETHRESEARCH 700 1- Fernandez Rodriguez Blanca M. joint author ETHRESEARCH 700 1- Minola Andrea joint author ETHRESEARCH 700 1- Sallusto Federica; id_orcid 0000-0003-3750-2752 joint author ETHRESEARCH 700 1- Luisetti Maurizio joint author ETHRESEARCH 700 1- Corti Davide joint author ETHRESEARCH 700 1- Lanzavecchia Antonio joint author ETHRESEARCH 773 0- Nature Communications London : Nature Publishing Group 6, p. 7375 2041-1723 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access