ABSTRACT
Pulmonary Alveolar Proteinosis (PAP) is characterized by the accumulation of surfactant
phospholipids and proteins within the alveoli of lungs. Currently, no specific therapy
exists for PAP, and sequential whole lung lavage is standard treatment. Over the past
5 years, important advances have been made in our understanding of alveolar proteinosis,
offering new directions for research as well as patient management. First, genetically
altered mice that are homozygous for a disrupted granulocyte-macrophage colony-stimulating
factor (GM-CSF) gene developed a lung lesion with histologic resemblance to PAP, along
with normal hematopoiesis. The biochemical properties of the material filling the
airspaces in these mutant mice are similar to those of patients with PAP. Surfactant
is thought to be cleared or catabolized mostly by alveolar macrophages, a process
dependent on GM-CSF. Second, a neutralizing autoantibody against GM-CSF was found
in bronchoalveolar lavage fluid and serum of patients with idiopathic PAP, but not
healthy controls. These observations raise the previously unsuspected notion that
human alveolar proteinosis may be an autoimmune disease, and suggest that GM-CSF antibody
has a potential role as a diagnostic test. The relationship between the antibody and
disease pathogenesis remains unknown. Additional data suggest that exogenous therapy
with GM-CSF may improve the lung disease in some patients with PAP. Intervention directed
at treating a relative GM-CSF deficiency or lowering the antibody (i.e., by plasmapheresis
or immunosuppression) may have promise in the therapy of this disease. Alveolar proteinosis
may be the first human disease wherein a circulating antibody against a growth factor
is linked to disease pathogenesis. Over a relatively short time, studies from ``knock-out''
mice have been translated to human studies for a new approach to diagnosis and therapy
for this disease.
KEYWORD
Pulmonary alveolar proteinosis - GM-CSF - surfactant - autoimmune disease - antibody
