Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA

Abstract

Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Rα) and nonbinding affinity-enhancing (GM-CSF-Rβ) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Rα–encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Rα, severely reducing GM-CSF binding, receptor signaling, and GM-CSF–dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.

Traitement de la protéinose alvéolaire par transplantation intrapulmonaire de macrophages

“…Le traitement hématologique, chimiothérapie et/ou la greffe de moelle, peut entraîner une guérison de la protéinose alvéolaire, en particulier au cours des leucémies aiguës [16]. Enfin le lavage thérapeu-tique pourrait être efficace au cours des protéinoses alvéolaires secondaires aux mutations de CSF2RA ou CSF2RB [17]. Le traitement par GM-CSF ne semble pas efficace [17][18][19].…”

“…Enfin le lavage thérapeu-tique pourrait être efficace au cours des protéinoses alvéolaires secondaires aux mutations de CSF2RA ou CSF2RB [17]. Le traitement par GM-CSF ne semble pas efficace [17][18][19]. L'évolution de la maladie n'est pas prévisible, et une rémission spontanée survient dans 5 à 7 % des cas.…”

Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer

“…lysed and evaluated by western blotting using the antibodies of pSTAT5 (Milipore) and STAT5 (SantaCruz) as described previously [12] . Phosphorylation of STAT5 was quantified by PathScan-STAT5(Y694) Sandwich ELISA Kit (Cell Signaling Technology).…”

“…Phosphorylation of STAT5 by post-aerosolised samples was calculated as % phosphorylation by pre-aerosolised samples. GM-CSF samples of a known concentration were used as calibration standards [12].…”

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

“…19,20 Subsequently PAP has been shown to be strongly associated with anti-GM-CSF autoantibodies, 21 or with mutations in either of the GM-CSF receptor subunits. [22][23][24][25] Additionally, transfer of auto-antibodies from patients with anti-GM-CSF-associated PAP to non-human primates led to the formation of foamy macrophages. 26 These results indicate that GM-CSF plays an important role in the terminal differentiation of alveolar macrophages in mice and humans.…”