Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis
Fregni, Chiara S.
Fernandez Rodriguez, Blanca M.
- Journal Article
Rights / licenseCreative Commons Attribution 4.0 International
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 Show more
Journal / seriesNature Communications
Pages / Article No.
PublisherNature Publishing Group
Organisational unit03856 - Lanzavecchia, Antonio (emeritus)
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