Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis

Piccoli, Luca; Campo, Ilaria; Fregni, Chiara Silacci; Fernandez Rodriguez, Blanca Maria; Minola, Andrea; Sallusto, Federica; Luisetti, Maurizio; Corti, Davide; Lanzavecchia, Antonio

doi:10.1038/ncomms8375

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Journal article

Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis

Piccoli, Luca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Microbiology, Eidgenoössische Technische Hochschule (ETH), Zürich 8093, Switzerland
Campo, Ilaria Respiratory Disease Unit, IRCCS San Matteo Hospital Foundation, Pavia 27100, Italy
Fregni, Chiara Silacci Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Fernandez Rodriguez, Blanca Maria Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Minola, Andrea Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Sallusto, Federica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Luisetti, Maurizio Respiratory Disease Unit, IRCCS San Matteo Hospital Foundation, Pavia 27100, Italy
Corti, Davide Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Humabs Biomed SA, Bellinzona 6500, Switzerland
Lanzavecchia, Antonio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Microbiology, Eidgenoössische Technische Hochschule (ETH), Zürich 8093, Switzerland

16.06.2015

Published in:

Nature communications. - 2015, vol. 6, p. 7375

English 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.

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