Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by myeloid cell dysfunction, progressive pulmonary surfactant accumulation, hypoxemia, innate immunodeficiency, and in some individuals, serious infections, pulmonary fibrosis, respiratory failure, and death.1 While PAP-causing diseases are clinically and mechanically heterogeneous, they are usefully categorized based on pathogenesis into primary, secondary, and congenital PAP. Primary PAP is caused by impaired granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent surfactant clearance by alveolar macrophages and accounts for about 90% of cases.2 Secondary PAP occurs as a consequence of a comorbid condition that impairs surfactant clearance by alveolar macrophages and accounts for about 5% to 10% of cases.3 Congenital PAP—more appropriately, surfactant metabolic dysfunction disorders—constitutes a clinically distinct and heterogeneous group of genetic diseases associated with acute respiratory failure at birth from surfactant deficiency/dysfunction or progressive pulmonary fibrosis, production of abnormal surfactant, and varying degrees of surfactant accumulation (hence, their consideration as PAP); these disorders account for less than 5% of cases.4 Importantly, research on the pathogenesis of primary PAP identified a critical role for GM-CSF in surfactant homeostasis, alveolar stability, lung function, and host defense. Because of its increased occurrence and greater research attention, primary PAP is the primary focus of this chapter; data for secondary and congenital PAP are provided when available.
In their 1958 report, Rosen et al.5 established that the material accumulating in alveoli in PAP was composed primarily of lipids with lesser amounts of proteins, and minimal carbohydrate. Subsequent research identified the material to be primarily surfactant (with an increased cholesterol-to-phospholipid ratio) with smaller amounts of uncleared cell debris and cytokines.6,7 In about 90% of patients, pathogenesis is driven by disruption of GM-CSF signaling to alveolar macrophages,1,8–10 which blocks their terminal differentiation in the lungs, their ability to clear surfactant, and a number of other functions.11–14
GM-CSF is a 23-kDa cytokine produced by respiratory epithelium and other cells,15–17 initially identified by its ability to stimulate the formation of macrophage and granulocyte colonies from hematologic progenitors and subsequently shown to stimulate functions in mature myeloid and other cells. While GM-CSF is similarly expressed in humans and mice and has remarkably similar regulatory effects on their respective target cell populations, the murine and human homologues are neither immunologically cross-reactive nor functionally interchangeable. GM-CSF binds to cell surface receptors composed of a GM-CSF–binding α-chain (CD116), an affinity-enhancing β-chain (CD131), and an associated Janus kinase 2 (JAK2). Ligand binding activates multiple intracellular signaling pathways including signal transducer and activator of transcription 5 (STAT5), regulating diverse functions of myeloid cells including survival, differentiation, proliferation, and host defense priming.17,18 GM-CSF also has regulatory effects on lymphocytes and alveolar epithelial cells.19–21
In primary PAP, pathogenesis is caused by disruption of GM-CSF signaling by neutralizing GM-CSF autoantibodies (autoimmune PAP) or by recessive mutations in CSF2RA or CSF2RB (encoding GM-CSF ...