A novel rodent model for autoimmune pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome caused by the accumulation of surfactants in the alveoli. The most prevalent clinical form of PAP is autoimmune (aPAP) whereby IgG autoantibodies neutralize the cytokine colony stimulating factor 2 (Csf2, formerly GM-CSF). Csf2 is a pleiotropic cytokine that promotes the differentiation, survival, and activation of alveolar macrophages (AM), the cells responsible for surfactant catabolism. IgG-mediated neutralization of Csf2 thereby inhibits AM homeostasis and function, leading to an innate immunodeficiency with increased susceptibility to opportunistic infections. Importantly, there are no rodent models for this disease, and therefore underlying immune mechanisms regulating Csf2-specific IgG in aPAP are not well understood. Herein, we identify autoimmune-prone Rasgrp1 -deficient (KO) mice as the first rodent model of aPAP: 1) analysis of lung sections revealed an eosinophilic, periodic acid Schiff positive proteinaceous accumulation in the alveoli; 2) KO mice exhibit reduced pulmonary compliance; 3) AM from KO mice are enlarged, exhibit impaired protein levels and have reduced surfactant degradation; and 4) serum Csf2-specific IgG are increased (ELISA) in KO mice. Finally, while control mice infected intranasally with Aspergillus fumigatus clear conidia readily, KO mice failed to clear conidia from the lungs. Collectively these data suggest that KO mice represent the first rodent model for aPAP.