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, Antonio Lanzavecchia

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Article number7375
JournalNature Communications
Volume6
DOIs
Publication statusPublished - Jun 16 2015

Fingerprint

Pulmonary Alveolar Proteinosis
clearances
Granulocyte-Macrophage Colony-Stimulating Factor
antibodies
Autoantibodies
bioassay
phenotype
macrophages
antigens
mutations
mice
molecular weight
safety
degradation
Antibodies
Bioassay
Autoantigens
Alveolar Macrophages
Patient Safety
Antigen-Antibody Complex

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Piccoli, L., Campo, I., Fregni, C. S., Rodriguez, B. M. F., Minola, A., Sallusto, F., ... Lanzavecchia, A. (2015). Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. Nature Communications, 6, [7375]. https://doi.org/10.1038/ncomms8375

Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. / Piccoli, Luca; Campo, Ilaria; Fregni, Chiara Silacci; Rodriguez, Blanca Maria Fernandez; Minola, Andrea; Sallusto, Federica; Luisetti, Maurizio; Corti, Davide; Lanzavecchia, Antonio.

In: Nature Communications, Vol. 6, 7375, 16.06.2015.

Research output: Contribution to journalArticle

Piccoli, L, Campo, I, Fregni, CS, Rodriguez, BMF, Minola, A, Sallusto, F, Luisetti, M, Corti, D & Lanzavecchia, A 2015, 'Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis', Nature Communications, vol. 6, 7375. https://doi.org/10.1038/ncomms8375
Piccoli, Luca ; Campo, Ilaria ; Fregni, Chiara Silacci ; Rodriguez, Blanca Maria Fernandez ; Minola, Andrea ; Sallusto, Federica ; Luisetti, Maurizio ; Corti, Davide ; Lanzavecchia, Antonio. / Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. In: Nature Communications. 2015 ; Vol. 6.
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