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Nat Commun. 2015 Jun 16;6:7375. doi: 10.1038/ncomms8375.

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

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1] Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland [2] Institute of Microbiology, Eidgenössische Technische Hochschule (ETH), Zürich 8093, Switzerland.
Respiratory Disease Unit, IRCCS San Matteo Hospital Foundation, Pavia 27100, Italy.
Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
1] Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland [2] Humabs Biomed SA, Bellinzona 6500, Switzerland.


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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