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Autoantibodies to multiple cytokines have been identified and some, including antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), have been associated with increased susceptibility to infection. High levels of GM-CSF autoantibodies that neutralize signaling cause autoimmune pulmonary alveolar proteinosis (aPAP), an ultrarare autoimmune disease characterized by accumulation of excess surfactant in the alveoli, leading to pulmonary insufficiency. Defective GM-CSF signaling leads to functional deficits in multiple cell types, including macrophages and neutrophils, with impaired phagocytosis and host immune responses against pulmonary and systemic infections. In this article, we review the role of GM-CSF in aPAP pathogenesis and pulmonary homeostasis along with the increased incidence of infections (particularly opportunistic infections). Therefore, recombinant human GM-CSF products may have potential for treatment of aPAP and possibly other infectious and pulmonary diseases due to its pleotropic immunomodulatory actions.

Pulmonary alveolar proteinosis (PAP) is a rare syndrome of alveolar surfactant accumulation, resulting hypoxemic respiratory failure, and increased infection risk. Despite advances in our understanding of disease pathogenesis and the availability of improved diagnostics, the epidemiology and healthcare burden of PAP remain poorly defined. To determine the prevalence, and healthcare utilization and costs associated with PAP, we interrogated a large health insurance claims database containing comprehensive data for approximately 15 million patients in the United States. We also evaluated data from a referral-based diagnostic testing program collected over a 15-year period. The prevalence of PAP was determined to be 6.87 ± 0.33 per million in the general population, similar in males and females, and increased with age, however considering difficulties and delays in diagnosing this is likely a minimum estimate of true prevalence. PAP patients had significantly more comorbidities, health care utilization and associated costs compared to control patients precisely matched for age and gender. Between 2004 and 2018, 249 patients confirmed to have PAP were evaluated to identify the PAP-causing disease; 91.5% had autoimmune PAP, 3% had hereditary PAP caused by GM-CSF receptor mutations, 4% had secondary PAP, and 1.5% had congenital PAP. Considering the high diagnostic accuracy of serum GM-CSF autoantibody testing and predominance of autoimmune PAP, these results emphasize the importance of utilizing blood-based testing in PAP syndrome to identify the PAP-causing disease rather than invasive lung biopsies, resulting in earlier diagnosis, reduced morbidity and lower healthcare costs.

Pulmonary alveolar proteinosis (PAP) is a syndrome of reduced GM-CSF-dependent, macrophage-mediated surfactant clearance, dysfunctional foamy alveolar macrophages, alveolar surfactant accumulation, and hypoxemic respiratory failure for which the pathogenetic mechanism is unknown. Here, we examine the lipids accumulating in alveolar macrophages and surfactant to define the pathogenesis of PAP and evaluate a novel pharmacotherapeutic approach. In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids. Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages. In Csf2rb −/− mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages. These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP. Pulmonary alveolar proteinosis (PAP) is associated with defective macrophage clearance of surfactant. Here, the authors show that patients with PAP have altered cholesterol-to-phospholipid ratio in their surfactant, and that more importantly, statin therapy and reduction of cholesterol accumulation in macrophages can ameliorate PAP in both humans and mice.

Desquamative interstitial pneumonia (DIP) is a rare, smoking-related, diffuse parenchymal lung disease characterized by marked accumulation of alveolar macrophages (AMs) and emphysema, without extensive fibrosis or neutrophilic inflammation. Because smoking increases expression of pulmonary GM-CSF (granulocyte/macrophage–colony stimulating factor) and GM-CSF stimulates proliferation and activation of AMs, we hypothesized that chronic exposure of mice to increased pulmonary GM-CSF may recapitulate DIP. Wild-type (WT) mice were subjected to inhaled cigarette smoke exposure for 16 months, and AM numbers and pulmonary GM-CSF mRNA levels were measured. After demonstrating that smoke inhalation increased pulmonary GM-CSF in WT mice, transgenic mice overexpressing pulmonary GM-CSF (SPC-GM-CSF+/+) were used to determine the effects of chronic exposure to increased pulmonary GM-CSF (without smoke inhalation) on accumulation and activation of AMs, pulmonary matrix metalloproteinase (MMP) expression and activity, lung histopathology, development of polycythemia, and survival. In WT mice, smoke exposure markedly increased pulmonary GM-CSF and AM accumulation. In unexposed SPC-GM-CSF+/+ mice, AMs were spontaneously activated as shown by phosphorylation of STAT5 (signal inducer and activator of transcription 5) and accumulated progressively with involvement of 84% (interquartile range, 55–90%) of the lung parenchyma by 10 months of age. Histopathologic features also included scattered multinucleated giant cells, alveolar epithelial cell hyperplasia, and mild alveolar wall thickening. SPC-GM-CSF+/+ mice had increased pulmonary MMP-9 and MMP-12 levels, spontaneously developed emphysema and secondary polycythemia, and had increased mortality compared with WT mice. Results show cigarette smoke increased pulmonary GM-CSF and AM proliferation, and chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP, including AM accumulation, emphysema, secondary polycythemia, and increased mortality in mice. These observations suggest pulmonary GM-CSF may be involved in the pathogenesis of DIP.

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–macrophage colony-stimulating factor (GM-CSF) autoantibodies occur in these patients 2 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 . . .

Abstract Rationale We identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony–stimulating factor (GM-CSF) receptor function, and increased GM-CSF. Objectives Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction. Methods We screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls. Measurement and Main Results Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy. Conclusions CSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage.

BackgroundInhaled molgramostim, a form of recombinant human granulocyte–macrophage colony stimulating factor (GM-CSF), is a promising investigational pharmacotherapy for autoimmune pulmonary alveolar proteinosis (aPAP); however, its pharmacology in healthy subjects has not been reported.MethodsThis randomised, double-blind, placebo-controlled, single-centre, phase 1 clinical trial assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy adults in single ascending dose (SAD) and multiple ascending dose (MAD) studies: one 150, 300 or 600 µg administration or six consecutive daily 300 or 600 µg administrations with evaluations over 28 or 34 days, respectively. The primary endpoint was safety, which was evaluated based on the number and severity of treatment-emergent AEs following single and multiple inhaled doses of molgramostim.Results42 subjects were enrolled including 18 in the SAD study and 24 in the MAD study; all completed the study. Inhaled molgramostim in healthy people was well tolerated and no dose-limiting safety concerns or anti-drug antibody formation were observed in either study. GM-CSF was measurable in serum 30 min after administration of inhaled molgramostim, peaked at 2 hours for all three doses and had an elimination half-life of 1.7±0.0 to 5.9±0.9 hours in the SAD and MAD studies. Systemic GM-CSF exposure was non-linear in both the SAD and MAD studies. Inhaled molgramostim caused a rapid increase in white blood cells (WBC) counts and leucocyte subsets that normalised by 8 hours (SAD) or 15–21 days (MAD). Fractional exhaled nitric oxide remained within the normal range at all doses but was numerically, but not significantly, increased at the 600 μg dose.ConclusionsIn healthy people, inhaled molgramostim was well-tolerated and resulted in systemic exposure at picogram levels, which had the expected PD effects on blood leucocyte levels that mostly remained within normal ranges.Trial registration numberNCT02468908; EudraCT No. 2013-001687-32

Abstract Rationale In patients with pulmonary alveolar proteinosis (PAP) syndrome, disruption of granulocyte/macrophage colony–stimulating factor (GM-CSF) signaling is associated with pathogenic surfactant accumulation from impaired clearance in alveolar macrophages. Objectives The aim of this study was to overcome these barriers by using monocyte-derived induced pluripotent stem (iPS) cells to recapitulate disease-specific and normal macrophages. Methods We created iPS cells from two children with hereditary PAP (hPAP) caused by recessive CSF2RAR217X mutations and three normal people, differentiated them into macrophages (hPAP-iPS-Mφs and NL-iPS-Mφs, respectively), and evaluated macrophage functions with and without gene-correction to restore GM-CSF signaling in hPAP-iPS-Mφs. Measurements and Main Results Both hPAP and normal iPS cells had human embryonic stem cell–like morphology, expressed pluripotency markers, formed teratomas in vivo, had a normal karyotype, retained and expressed mutant or normal CSF2RA genes, respectively, and could be differentiated into macrophages with the typical morphology and phenotypic markers. Compared with normal, hPAP-iPS-Mφs had impaired GM-CSF receptor signaling and reduced GM-CSF–dependent gene expression, GM-CSF– but not M-CSF–dependent cell proliferation, surfactant clearance, and proinflammatory cytokine secretion. Restoration of GM-CSF receptor signaling corrected the surfactant clearance abnormality in hPAP-iPS-Mφs. Conclusions We used patient-specific iPS cells to accurately reproduce the molecular and cellular defects of alveolar macrophages that drive the pathogenesis of PAP in more than 90% of patients. These results demonstrate the critical role of GM-CSF signaling in surfactant homeostasis and PAP pathogenesis in humans and have therapeutic implications for hPAP.

Infection, especially with opportunistic microbes, is a prominent feature of pulmonary alveolar proteinosis; extrapulmonary infection suggests a systemic susceptibility. The authors show that neutrophil functions (phagocytosis, adhesion, oxidative burst, and bactericidal activity) are depressed in patients with pulmonary alveolar proteinosis and that the cause is autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). These findings clearly demonstrate the essential role of GM-CSF in the antimicrobial activities of neutrophils. The authors show that neutrophil functions are depressed in patients with pulmonary alveolar proteinosis and that the cause is autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). Pulmonary alveolar proteinosis 1 is a rare disorder in which surfactant accumulates within pulmonary alveoli, causing respiratory insufficiency. 2 , 3 The disease is specifically associated with high levels of autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF) in blood and tissues, including pulmonary alveoli. 4 These autoantibodies neutralize the biologic activity of GM-CSF. 5 In mice, GM-CSF stimulates the terminal differentiation of alveolar macrophages, primarily through the action of the transcription factor PU.1. 6 The homozygous deletion of GM-CSF genes causes pulmonary alveolar proteinosis in mice 7 , 8 by impairing the clearance of pulmonary surfactant by alveolar macrophages that are dependent on GM-CSF. 9 In patients with pulmonary alveolar . . .

Abstract Rationale Granulocyte/macrophage colony–stimulating factor (GM-CSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals. Objectives Our primary objective was to determine whether human GMAb would reproduce PAP in healthy primates. A secondary objective was to determine the concentration of GMAb resulting in loss of GM-CSF signaling in vivo (i.e., critical threshold). Methods Nonhuman primates (Macaca fascicularis) were injected with highly purified, PAP patient-derived GMAb in dose-ranging (2.2–50 mg) single and multiple administration studies, and after blocking antihuman immunoglobulin immune responses, in chronic administration studies maintaining serum levels greater than 40 μg/ml for up to 11 months. Measurements and Main Results GMAb blocked GM-CSF signaling causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids and proteins; (2) enlarged, foamy, surfactant-filled alveolar macrophages with reduced PU.1 and PPARγ mRNA, and reduced tumor necrosis factor-α secretion; (3) pulmonary leukocytosis; (4) increased serum surfactant protein-D; and (5) impaired neutrophil functions. GM-CSF signaling varied inversely with GMAb concentration below a critical threshold of 5 μg/ml, which was similar in lungs and blood and to the value observed in patients with PAP. Conclusions GMAb reproduced the molecular, cellular, and histopathologic features of PAP in healthy primates, demonstrating that GMAb directly cause PAP. These results have implications for therapy of PAP and help define the therapeutic window for potential use of GMAb to treat other disorders.