Piccoli, Luca Campo, Ilaria Fregni, Chiara Silacci Fernandez Rodriguez, Blanca Maria Minola, Andrea Sallusto, Federica Luisetti, Maurizio Corti, Davide Lanzavecchia, Antonio 2015-06-16 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. application/pdf https://susi.usi.ch/global/documents/319063 https://localhost:5000/ark:/12658/srd1319063 https://susi.usi.ch/documents/319063/files/Piccoli_NC_2015.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms8375 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319063 info:eu-repo/semantics/openAccess CC BY Nature communications. - 2015, vol. 6, p. 7375 Autoimmune diseases Cytokines Mucosal immunology Respiratory tract diseases info:eu-repo/classification/udc/61 Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis http://purl.org/coar/resource_type/c_6501