Etiology for idiopathic pulmonary alveolar proteinosis : Roles of the autoantibody against GM-CSF in the pathogenesis.

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Mice deficient in either GM-CSF or its receptor develop pulmonary alveolar proteinosis (PAP), which is a diseases characterized by accumulation of excessive surfactant composed of phospholipids and surfactant proteins in the alveoli and terminal bronchioli, pointing to a role for GM-CSF in the pathogenesis of PAP. Thus, in this model, lack of GM-CSF signaling produces AM dysfunction leading to PAP. This conclusion is strongly supported by the observation that PAP in the receptor knockout mouse was corrected by bone marrow transplantation from wild type mice and PAP in the cytokine knock out mouse was corrected by transgenic expression of GM-CSF in the pulmonary epithelia. The relationship of the mouse model of PAP to human idiopathic PAP, the most common acquired form of unknown etiology, remains to be elucidated. Recently, we found a factor in the bronchoalveolar lavage fluid (BALF) from IPAP patients that neutralizes the bioactivity of GM-CSF. The factor directly binds to GM-CSF and blocks the binding to GM -CSF receptor on cells. Here, we describe that the factor is a neutralizing auto-antibody directed against GM-CSF in the BALF and sera of patients with IPAP. Our data suggest that IPAP patients have disruption of GM-CSF signaling similar to the mouse model of PAP. In the human disease, however, GM-CSF signaling is abolished by a neutralizing auto-antibody. These findings may promote a rational development of future therapies to lower levels of auto-antibody against GM-CSF in the lung in IPAP patients.