Extra-pulmonary aspects of acquired pulmonary alveolar proteinosis as predicted by granulocyte-macrophage...

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-/- mice are an invaluable model for exploring the effects of systemic GM-CSF deficiency. Their lung phenotype exactly reproduces the abnormalities seen in human pulmonary alveolar proteinosis (PAP). However, GM-CSF-/- mice also have significant systemic functional abnormalities. These include immune defects which result in a reduced susceptibility to a range of experimentally induced autoimmune disorders. These immunological defects are also functionally manifest as an impaired ability to resolve a range of infections under certain conditions, usually implicating cellular effectors, including Listeria, Group B streptococcus, adenovirus, Pneumocystis carinii, and malaria. These observations are consistent with the known propensity for patients with PAP to develop a range of opportunistic infections. Conversely, the diminished immunological response to inflammatory stimuli may be beneficial in some settings by limiting inflammatory cell recruitment and pro-inflammatory mediator-release. GM-CSF-/- mice also have distinct fertility defects, manifest as reduced litter size and an increased rate of early fetal loss. These observations may be clinically relevant for women affected by PAP and further support the evaluation of the role of GM-CSF in human reproduction. These observations reinforce the importance of clinicians viewing PAP as a state of systemic functional GM-CSF deficiency, albeit with prominent pulmonary manifestations, rather than purely a 'lung disease'. These systemic manifestations of GM-CSF deficiency should also be considered when deciding on the choice between pulmonary or systemic delivery of GM-CSF as therapy for PAP, as only systemic drug delivery has the potential capacity to correct the systemic manifestations of GM-CSF deficiency in these patients.