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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antibodies, Neutralizing / immunology*
  • Autoantibodies / immunology*
  • Autoimmune Diseases / immunology*
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / genetics
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Pulmonary Alveolar Proteinosis / immunology*
  • Receptors, IgG / immunology

Substances

  • Antibodies, Neutralizing
  • Autoantibodies
  • Epitopes
  • Receptors, IgG
  • Granulocyte-Macrophage Colony-Stimulating Factor

Supplementary concepts

  • Pulmonary Alveolar Proteinosis, Acquired