Human GM-CSF Autoantibodies and Reproduction of Pulmonary Alveolar Proteinosis

To the Editor: Idiopathic pulmonary alveolar proteinosis is a rare disease in which surfactant lipids and proteins accumulate in pulmonary alveolar macrophages and alveoli, resulting in respiratory insufficiency and, in severe cases, respiratory failure.1 Granulocyte\u96macrophage colonystimulating factor (GM-CSF) autoantibodies occur in these patients2 and may mediate the pathogenesis of this disease, but they are also present in healthy persons and in immune globulin prepared from plasma obtained from healthy persons. Since GM-CSF is required for surfactant catabolism by alveolar macrophages in mice, we hypothesized that high levels of GM-CSF autoantibodies (i.e., levels sufficient to eliminate endogenous GM-CSF priming of myeloid cells) could cause idiopathic pulmonary alveolar proteinosis by impairing surfactant clearance by alveolar macrophages.3 We previously found that high levels of GM-CSF autoantibodies are specifically associated with idiopathic pulmonary alveolar proteinosis4 and can be isolated in pure form from these patients.5 We administered highly purified GM-CSF autoantibodies derived from a patient with idiopathic pulmonary alveolar proteinosis to healthy nonhuman primates (Macaca fascicularis). These autoantibodies were administered intravenously, and serum levels of 40 \ub5g per milliliter or more were maintained for 10 months. A marked reduction in levels of GM-CSF\u96stimulated CD11b in blood leukocytes indicated that GM-CSF signaling was blocked; these results were identical to those in patients with idiopathic pulmonary alveolar proteinosis.