Idiopathic Pulmonary Alveolar Proteinosis as an Autoimmune Disease with Neutralizing Antibody against Granulocyte/Macrophage Colony-Stimulating Factor

TLDR

Idiopathic pulmonary alveolar proteinosis is a rare disease of unknown etiology characterized by lipoproteinaceous material filling the alveoli, and loss of GM‑CSF signaling has been shown to cause similar disease in congenital cases and animal models. The study reports that I‑PAP is an autoimmune disease driven by a neutralizing IgG antibody against GM‑CSF. All 11 I‑PAP patients had anti‑GM‑CSF IgG in bronchoalveolar lavage and serum, which binds and neutralizes GM‑CSF, whereas it was absent in secondary PAP, normal subjects, and other lung diseases, supporting a pathogenic role for antibody‑mediated GM‑CSF inhibition in surfactant clearance failure.

Abstract

Idiopathic pulmonary alveolar proteinosis (I-PAP) is a rare disease of unknown etiology in which the alveoli fill with lipoproteinaceous material. We report here that I-PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against granulocyte/macrophage colony-stimulating factor (GM-CSF). The antibody was found to be present in all specimens of bronchoalveolar lavage fluid obtained from 11 I-PAP patients but not in samples from 2 secondary PAP patients, 53 normal subjects, and 14 patients with other lung diseases. It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro. The antibody was also found in sera from all I-PAP patients examined but not in sera from a secondary PAP patient or normal subjects, indicating that it exists systemically in I-PAP patients. As lack of GM-CSF signaling causes PAP in congenital cases and PAP-like disease in murine models, our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance.