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

Luca Piccoli, Ilaria Campo, Chiara Silacci Fregni, Blanca Maria Fernandez Rodriguez, Andrea Minola, Federica Sallusto, Maurizio Luisetti, Davide Corti and Antonio Lanzavecchia ()
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Luca Piccoli: Institute for Research in Biomedicine (IRB)
Ilaria Campo: Respiratory Disease Unit, IRCCS San Matteo Hospital Foundation
Chiara Silacci Fregni: Institute for Research in Biomedicine (IRB)
Blanca Maria Fernandez Rodriguez: Institute for Research in Biomedicine (IRB)
Andrea Minola: Institute for Research in Biomedicine (IRB)
Federica Sallusto: Institute for Research in Biomedicine (IRB)
Maurizio Luisetti: Respiratory Disease Unit, IRCCS San Matteo Hospital Foundation
Davide Corti: Institute for Research in Biomedicine (IRB)
Antonio Lanzavecchia: Institute for Research in Biomedicine (IRB)

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8375

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