Idiopathic Pulmonary Alveolar Proteinosis Research Articles

Pulmonary Alveolar Proteinosis

Abstract: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of surfactant phospholipids and proteins in the alveoli (Trapnell et al, N Engl J Med. 2003;349:2527–2539). Less than 500 separate cases of PAP have been reported in the literature from the time of first description in 1958. These reports suggest an annual incidence of 0.36 and prevalence of 3.7 cases per million population (Seymour et al, Am J Respir Crit Care Med. 2002;166:215–235). The clinical course of PAP ranges from spontaneous resolution to death because of superimposed infection or respiratory failure. A number of important milestones mark the key advances in the study of this disease, which have led to an improved classification based on pathogenesis. In the last decade, the serendipitous finding of a lung disease reminiscent of PAP in transgenic granulocyte-macrophage colony-stimulating factor knockout mice (GM-CSF−/−) led to the link between GM-CSF and PAP (Dranoff et al. Science. 1994;264:713–716; Stanley et al. Proc Natl Acad Sci USA. 1994;91:5592–5596). The finding of neutralizing antibodies to GM-CSF suggest an autoimmune basis to idiopathic PAP (Kitamura et al. J Exp Med. 1999;190:875–880). These findings have resulted in innovative treatment approaches to enhance the current standard of care. This review summarizes some of these landmark studies and provides a rationale and plan for investigations that lead to the diagnosis, classification, and management of PAP.

Lung cancer may develop subsequently or coincidently with pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by an accumulation of periodic acid-Schiff (PAS) positive lipoproteinaceous material in the alveolar space. It is usually idiopathic, and secondary to hematologic malignancy or some atypical infection. To date, there are only five published case reports of PAP occurring in association with solid organ cancer. We herein report two cases of PAP associated with lung cancer: one, a case of idiopathic PAP with subsequent development of lung cancer, and the other, a case of coexisting lung cancer and PAP. In conclusion, PAP can occur prior to or coincidently with lung cancer.

Elevated BALF concentrations of α- and β-defensins in patients with pulmonary alveolar proteinosis

Defensins are endogenous antibiotics and regulators of inflammation, immunity and wound repair. Their concentrations are substantially increased in bronchoalveolar lavage fluid (BALF) of patients with infectious lung diseases. alpha-defensin (HAD) levels are also elevated in patients with idiopathic pulmonary fibrosis (IPF) and correlated with the decline in pulmonary function tests, suggesting the association of defensins with the pathogenesis of interstitial lung diseases. The aim of this study was to determine the profile of defensins in interstitial lung diseases. Serum and BALF levels of HAD and beta-defensin 1 and 2 (HBD-1, and -2) were measured by radioimmunoassay in 63 patients with interstitial lung diseases, including idiopathic pulmonary alveolar proteinosis (PAP), IPF, nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) and pulmonary sarcoidosis, and in 9 healthy volunteers as controls. Levels of HAD in BALF of patients with PAP were significantly higher than those in controls and patients with COP and sarcoidosis. Serum levels of HAD in all groups were significantly higher than those in controls. Levels of HBD-1 and -2 in BALF of patients with PAP were extremely high in all subjects. Serum levels of HBD-1 were higher in all patient groups, with the exception of those with PAP, and those of HBD-2 were also higher in patients with IPF and sarcoidosis, compared with controls. BALF of PAP patients, but not IPF patients and controls, expressed antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. Our findings suggest different kinetics of HAD and HBD-1 and -2 in serum and BALF of interstitial lung diseases and that these antimicrobial peptides in the airway lumen may contribute to prevention of bacterial airway infections in PAP.

An Open-Label Trial of Granulocyte Macrophage Colony Stimulating Factor Therapy for Moderate Symptomatic Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare idiopathic autoimmune lung disease in adults characterized by the accumulation of lipoproteinaceous material within the alveoli of the lung. The natural history of this disease is poorly defined. Current therapy of bilateral whole-lung lavage (WLL) under general anesthesia is invasive and has its limitations. Data suggest that relative granulocyte macrophage colony stimulating factor (GM-CSF) deficiency may be involved in the pathogenesis of this disease. There have been several case series that have described clinical improvement with exogenous GM-CSF therapy in a subset of patients with PAP. We describe the results of a prospective, open-label clinical trial of daily subcutaneous GM-CSF therapy in a group of adult patients with idiopathic PAP. In this series of 25 patients, the largest reported to date, administration of GM-CSF improved oxygenation as assessed by a 10 mm Hg decrease in alveolar-arterial oxygen gradient, as well as improvement in other clinical and quality of life parameters in 12 of 25 patients (48%) with moderate symptomatic disease who completed the trial. In addition, the serum anti-GM-CSF antibody titer correlated with lung disease activity and was a predictor for responsiveness to therapy. These data indicate that subcutaneous GM-CSF therapy is a promising alternative to WLL for symptomatic patients with PAP.

Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis

Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) auto-antibodies have been found in many patients with pulmonary alveolar proteinosis (PAP). The present study reports a retrospective case series of patients who used aerosolised GM-CSF in the treatment of idiopathic PAP. Between 1999 and 2003, 12 patients elected to receive aerosolised GM-CSF (250 microg b.i.d. every other week) in lieu of whole-lung lavage or observation. Patient characteristics, pulmonary function tests, arterial blood gas analysis, laboratory values and chest radiographs were extracted from the patient's medical records. Of the six patients tested, all had GM-CSF neutralising antibodies. Additionally, abnormalities in GM-CSF gene expression (one patient), receptor expression (two patients) and ability to upregulate adhesion molecules (one patient) were found. All patients except one had a positive response (mean improvements in arterial oxygen tension, alveolar-arterial oxygen gradient, carbon monoxide diffusing capacity of the lung and forced vital capacity were 17.1 mmHg, 18.4 mmHg, 16.6% pred and 13.5% pred, respectively). Two patients made a complete recovery and were disease free 1 and 2 yrs after discontinuing treatment. Four patients showed complete response to both the initial course or when treated again for recurrence after discontinuation of treatment. One patient required dose escalation (500 microg b.i.d.) with complete response. GM-CSF was well tolerated without late toxicity after median (range) follow-up of 30.5 (3-68) months. In conclusion, aerosolised granulocyte-macrophage colony-stimulating factor is safe and effective in treating pulmonary alveolar proteinosis providing an alternative to whole-lung lavage or subcutaneous granulocyte-macrophage colony-stimulating factor.

Epidemiological and clinical features of idiopathic pulmonary alveolar proteinosis in Japan

Idiopathic pulmonary alveolar proteinosis (IPAP) is a rare disease characterized by excessive amounts of lipoproteinaceous material in the alveolus. This report presents an interim analysis of nationwide epidemiological data from Japanese patients with pulmonary alveolar proteinosis, and the roles of serum markers for IPAP. (i) The nationwide demographic data from 166 Japanese patients with IPAP are shown. The female to male ratio was 1:2, and the average age was 51 +/- 14 years old (age range: 15-79 years) at registration or diagnosis. A total of 30% of patients with IPAP have a poor clinical course. In total, 30% of patients were treated with whole lung lavage therapy (WLL). Under WLL, the patients significantly improved in the short term, but 40% of the patients who underwent WLL worsened again. A new strategy such as granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for intractable PAP is required. (ii) The correlation of serum KL-6, carcinoembryonic antigen, surfactant proteins D and A, and LDH with disease severity suggests their potential as disease markers. In contrast, serum anti-GM-CSF antibody did not correlate with disease severity, but is a specific marker for the diagnosis of IPAP. The combined measurements of the serum markers may well prove very useful for both the diagnosis and the management of IPAP patients.

Granulocyte‐macrophage colony‐stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long‐term treatment with aerosolized granulocyte‐macrophage colony‐stimulating factor: a case report

Idiopathic pulmonary alveolar proteinosis (IPAP) is considered to be caused by an autoantibody to the granulocyte-macrophage colony-stimulating factor (GM-CSF), which neutralizes GM-CSF and therefore impairs the differentiation of alveolar macrophages. The authors have previously characterized the BAL fluid and alveolar macrophages obtained from three IPAP patients who were successfully treated with aerosolized GM-CSF and demonstrated restoration of the cell number, expression of surface marker, and phagocytic ability of the alveolar macrophages as well as a decrease in the autoantibody levels in the BAL fluid. The condition recurred in one of the patients after 20 months. This patient underwent a second and third course of GM-CSF inhalation therapy with the same dose and schedule as the first one. Since the second therapeutic intervention did not succeed in producing any improvement in the symptoms and disease markers, the authors used a new nebulizer and a liquid preparation of the drug instead of the lyophilized preparation for the third therapeutic session and this restored the respiratory function considerably. A 6-month maintenance therapeutic regimen with a lower GM-CSF inhalation frequency brought about a further improvement in the disease markers. The results suggest that the efficacy of GM-CSF inhalation therapy might be related to the drug preparation mode, choice of nebulizer, and duration of treatment.

Serum Antibody Against Granulocyte/Macrophage Colony-Stimulating Factor and KL-6 in Idiopathic Pulmonary Alveolar Proteinosis

Here we describe a case of idiopathic pulmonary alveolar proteinosis (I-PAP), in which anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) antibody and high level of KL-6 were found in the serum. Anti-GM-CSF antibody is responsible for I-PAP, and KL-6 is a serum marker for the activity of diffuse interstitial lung disease. A 38-year-old woman, who had no symptoms, was found to have an abnormal shadow on chest radiograph 5 years previously at a health check up. Chest radiograph showed a patchy shadow in the left lower lung field. Thoracoscopic biopsy was performed because the shadow had gradually expanded during the 5 years. Histological examination revealed proteinous material filling the alveoli and positive staining by the PAS method, suggesting PAP. Anti-GM-CSF antibody and a high level of KL-6 were detected in the serum at the time of diagnosis. Three years later, the shadow disappeared spontaneously. During this period, the level of KL-6 dramatically decreased, although that of GM-CSF antibody remained unchanged. The present case suggests that the serum level of the anti-GM-CSF antibody represents a useful marker for the diagnosis but not for follow-up of the clinical course. On the contrary, KL-6 is an excellent marker for the assessment of the clinical course of I-PAP.

Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration

The authors report a female patient with congenital pulmonary alveolar proteinosis (PAP). She had two brothers who died from the same disease. BAL did not improve her progressive respiratory failure. After intravenous immunoglobulin G (IVIG) administration for complicated hypogammaglobulinemia, she recovered from respiratory failure. The efficacy of IVIG was confirmed by recovery from deterioration in respiratory status and improvement in chest CT findings on two separate occasions. Subsequently, the patient remains free from respiratory symptoms for more than 3 years on an ongoing regimen of monthly IVIG. She had no surfactant protein (SP) B deficiency. Alveolar macrophages (AM) obtained from her BAL fluid were small and showed decreased phagocytotic activity. Immunostaining revealed weak expression of PU.1 in her AM, a key protein in AM maturation. All nucleotide sequences of granulocyte-macrophage colony stimulating factor (GM-CSF), GM-CSF-receptor and PU.1 were normal. Endotoxin-induced GM-CSF release from peripheral mononuclear cells (PMNC), and proliferation of PMNC in response to GM-CSF were normal. In addition, an antibody against GM-CSF, as seen in adult patients with idiopathic PAP, was not detected in the serum or BAL fluid. Although the patient's PMNC secreted only small amounts of IgG and IgM, an EB virus-derived cell line of her B cells secreted IgM as much as normal control cells. In a flow cytometric study, IgM was expressed on the cell surface. In conclusion, an abnormality in a single gene may have decreased secretion of immunoglobulin from the B cells and the AM phagocytotic activity in the patient.

Why does the autoantibody against granulocyte‐macrophage colony‐stimulating factor cause lesions only in the lung?

During the course of investigating the etiology of idiopathic pulmonary alveolar proteinosis (IPAP), the authors found that the autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) was consistently present in both sera and the lung tissue. The autoantibody completely blocked bioactivity by direct binding with high specificity and avidity. Because of the existence of patients with congenital PAP who lack GM-CSF receptors and the development of PAP in GM-CSF and GM-CSF receptor knock-out mice, the autoantibody is likely to be the causative agent for IPAP. However, this finding posed the question as to why the autoantibody against GM-CSF caused lesions only in the lung. To answer this question, the authors investigated, using immunohistochemistry, confocal laser microscopy, and immunoblotting, the expression of PU.1 in tissue macrophages. PU.1 is a critical transcription factor for terminal differentiation of alveolar macrophage (AM), as reported previously in the lung, liver, spleen, kidney, intestine and brain. PU.1 was consistently expressed in the nuclei of normal AM, but faintly or not at all in IPAP-AM. Moreover, it was not expressed in the nuclei of any other normal tissue macrophages tested. Blood monocytes expressed PU.1 in the cytosol but not in the nuclei. These results suggested that the differentiation pathway is different between AM and other tissue macrophages. PU.1 was not expressed in the nuclei of newborn rat lung AM but was gradually expressed during the first 10 days. The authors demonstrated that GM-CSF is crucial for terminal differentiation of AM, but not for that of other tissue macrophages.

Effect of Body Position on Gas Exchange in Patients With Idiopathic Pulmonary Alveolar Proteinosis: No Benefit of Prone Positioning

<h3>Background</h3> Prone positioning may improve oxygenation in patients with acute lung injury/ARDS. However, the beneficial effect of prone positioning on gas exchange has never been investigated in patients with diffuse pulmonary infiltrates who breathe spontaneously <h3>Objective</h3> To evaluate the effect of body position on gas exchange in patients with idiopathic pulmonary alveolar proteinosis (PAP) with special reference to the benefit of prone positioning <h3>Design</h3> A prospective study <h3>Setting</h3> Tertiary medical center <h3>Patients and methods</h3> Eight patients with PAP were studied on 25 occasions using spirometry, body plethysmography, and single-breath diffusing capacity of the lung for carbon monoxide (Dlco). Arterial blood gas levels were measured in the sitting position and in four lying positions randomly while patients breathed room air. To serve as control subjects, 16 age-matched healthy hospital personnel were studied. To evaluate the impact of oxygen therapy on positional effect in gas exchange, arterial blood gas levels were measured in the supine and prone positions in some PAP patients while breathing 40% oxygen <h3>Results</h3> Normal to varying degrees of restrictive ventilatory defect and gas exchange impairment, as evidenced by Dlco, Pao₂, and alveolar-arterial oxygen pressure difference (P[A-a]O₂), were found in PAP patients. The ventilatory function parameters correlated positively with Pao₂ and negatively with P(A-a)O₂. The values of Pao₂ and P(A-a)O₂ measured in four lying positions showed no significant difference in both PAP patients and healthy control subjects. Furthermore, the differences in Pao₂ and P(A-a)O₂ between measurements made in the supine and prone positions and the ratio of Pao₂ measured in the prone position/Pao₂ measured in the supine position were comparable between PAP patients and healthy control subjects. Arterial blood gas levels showed no significant difference between measurements made in PAP patients in the supine and prone positions while breathing 40% oxygen <h3>Conclusions</h3> Positional change did not significantly affect gas exchange, and no benefit of prone positioning was found in both PAP patients and healthy control subjects. Further studies are needed to verify the benefit of prone ventilation in patients with diffuse pulmonary disorders who breathe spontaneously

Granulocyte-Macrophage Colony–Stimulating Factor and Lung Immunity in Pulmonary Alveolar Proteinosis

The anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GM-CSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages.

Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF

Existence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibody and treatment with recombinant GM-CSF are new topics in idiopathic pulmonary alveolar proteinosis (PAP). We have hypothesized inhaled GM-CSF is effective and neutralizing capacity of GM-CSF, not concentration of anti-GM-CSF antibody in serum reflect disease severity. A 57-year-old female smoker with idiopathic PAP was treated with inhaled GM-CSF. The response to the treatment was evaluated by diffusing capacity for carbon monoxide (DLCO), alveolar-arterial oxygen gradient ([A-a]DO2). Conventional serum markers, including KL-6, surfactant apoprotein (SP)-A, SP-D, carcino-embryonic antigen and cytokeratin fragment 19 (CYFRA), and concentration of anti-GM-CSF antibody were examined. The neutralizing capacity of GM-CSF in serum was evaluated using a GM-CSF dependent cell line, TF-1. Ground glass opacity disappeared at the end of the treatment. Her DLCO, [A-a]DO2 remarkably improved after treatment. The neutralizing capacity of GM-CSF declined in line with disease remission and it correlated significantly with DLCO (P = 0.0137). The concentration of anti-GM-CSF antibody had no significant relation with disease severity and serum markers including neutralizing capacity. Conventional serum markers other than CYFRA showed no significant correlation with Inhaled GM-CSF was effective for idiopathic PAR Serial measurement of neutralizing capacity of GM-CSF was useful to evaluate disease severity and the anti-GM-CSF antibody was proved to be a causative factor for PAR In the future, inhaled GM-CSF may replace whole lung lavage and response to GM-CSF and its optimal amount may be decided by the capacity.

Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis

Whole lung lavage (WLL) is still the gold-standard therapy for pulmonary alveolar proteinosis (PAP). The few studies on the duration of the effect of WLL, belonging to a rather remote period, show significant but transient benefits. In 21 patients with idiopathic PAP, the duration of any benefit and, in 16 of them, the time course of lung function improvement (at baseline, 1 week, 6 months, 1 yr and then every 2 yrs after WLL) were evaluated. The present WLL technique takes longer, is invasively monitored and partially modified with respect to past techniques. More than 70% of patients remained free from recurrent PAP at 7 yrs. The bulk of the improvement in spirometric results was almost completely gained in the immediate post-WLL period due to the efficient clearance of the alveoli. At a median of 5 yrs, recovery of diffusing capacity of the lung for carbon monoxide was incomplete (75 +/- 19% of the predicted value) and there were residual gas exchange abnormalities (alveolar to arterial oxygen tension difference 3.6 +/- 1.5 kPa (27 +/- 11 mmHg)) and exercise limitation, probably explained by engorgement of lymphatic vessels. In conclusion, whole lung lavage for idiopathic pulmonary alveolar proteinosis is currently a safe procedure in an experienced setting, and provides long-lasting benefits in the majority of patients.

Pulmonary alveolar proteinosis. Clinical manifestations and optimal treatment strategies.

Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of surfactant phospholipids and proteins within the lung alveoli. Important advances have been made over the past 8 years in our understanding of this disease, offering new directions for research and patient care. 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. The surfactant is thought to be catabolized or cleared mostly by alveolar macrophages, this process being dependent on GM-CSF. Second, a neutralizing autoantibody against GM-CSF was found in serum and bronchoalveolar lavage fluid of patients with idiopathic PAP but not in healthy controls, thereby raising the suspicion that human PAP may be an autoimmune disease. The relationship between the antibody and disease pathogenesis remains unclear but data suggest that the GM-CSF antibody may have a potential role as a diagnostic test. No specific therapy exists for PAP. Sequential whole lung lavage is the standard of care. Exogenous therapy with GM-CSF may improve the lung disease in some patients with PAP but this therapy is still experimental. Interventions directed at treating a relative GM-CSF deficiency by administration of GM-CSF or lowering the antibody level (i.e. by plasmapheresis or immunosuppression) may hold promise as future therapy for this rare disease.

Anti-GM-CSF Titer Predicts Response to GM-CSF Therapy in Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is an idiopathic disease characterized by the accumulation of surfactant in the pulmonary airspaces. The development of a PAP-like syndrome in the GM-CSF knockout mouse and resolution of disease by local GM-CSF expression strongly implicates GM-CSF in surfactant homeostasis and disease pathogenesis. Based on murine data, GM-CSF therapy was administered to PAP patients, with a subset responding to therapy. The lack of response to GM-CSF therapy in some patients is unexplained. In adult idiopathic PAP there appears to be no intrinsic cellular defect in synthesizing or secreting GM-CSF and/or function in the GM-CSF receptor. Subsequent studies have shown the presence of circulating, neutralizing anti-GM-CSF antibodies in all adult PAP patients studied to date. Whether the anti-GM-CSF is causally related to the PAP disease and whether it should be the target of manipulation remains to be determined. The present study quantified the anti-GM-CSF levels sequentially in PAP patients receiving GM-CSF therapy. The data indicate that titers of circulating anti-GM-CSF predict response to GM-CSF therapy. In addition, we present data from a patient undergoing plasmapheresis in which anti-GM-CSF titer decreased with improvement in the lung disease. Together, these data support the hypothesis that PAP is an anti-GM-CSF autoimmune disease due to the development of antibodies, which results in the deactivation or neutralization of GM-CSF.

Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of phospholipids and surfactant proteins in the lung. The central role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in surfactant homeostasis has been established in mice lacking the GM-CSF gene, which results in murine pulmonary alveolar proteinosis. No GM-CSF gene defect has been defined in adult patients with idiopathic PAP. Previous studies indicated that the human disease differs from the murine model by the presence of circulating, neutralizing autoantibodies against GM-CSF. Therefore, the final common pathway between the GM-CSF knockout and human PAP appears to be the deficiency of functionally active GM-CSF. In the present study, all patients with idiopathic PAP were found to have systemic and localized antibodies against GM-CSF. Anti-GM-CSF titers were a specific and sensitive marker for PAP. In addition, we present data showing that the absence of active GM-CSF is associated with enhanced levels of macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and interleukin-8. These studies confirm and strengthen previous studies and support the concept that adult idiopathic PAP is an autoimmune disease defined by the presence of anti-GM-CSF. Further, using anti-GM-CSF as an indicator of pulmonary alveolar proteinosis may avoid the use of more invasive means of evaluating patients with pulmonary disease characterized by alveolar infiltrates.

Pulmonary Alveolar Proteinosis: Recent Advances

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.

Pulmonary alveolar proteinosis is a disease of decreased availability of GM-CSF rather than an intrinsic cellular defect.

Granulocyte-macrophage colony stimulating factor (GM-CSF) deficient mice develop a pulmonary alveolar proteinosis (PAP) syndrome which is corrected by the administration/expression of GM-CSF. These observations implicate GM-CSF in the pathogenesis of human PAP. We hypothesized that human PAP may involve an intrinsic cellular defect in monocytes/macrophages with an inability to produce GM-CSF and/or respond to GM-CSF. Thus, we investigated the cytokine responses to GM-CSF and LPS from peripheral blood monocytes and alveolar macrophages from patients with idiopathic PAP and healthy controls. Macrophage inflammatory protein-1-alpha (MIP) was measured from GM-CSF-stimulated cells and GM-CSF was measured from LPS-stimulated cells by ELISA. The MIP and GM-CSF production by monocytes and alveolar macrophages did not differ between PAP patients and healthy controls. Growth of the GM-CSF-dependent human myeloid cell line TF-1 was inhibited by serum from all patients studied (n = 10) and all patients had anti-GM-CSF antibody in their serum. The BAL from PAP patients had less detectable GM-CSF by ELISA than healthy controls (P = 0.05); in contrast, the inhibitory cytokine, interleukin-10 (IL-10), was increased in PAP compared to controls (P = 0.04). IL-10 is a potent inhibitor of LPS-stimulated GM-CSF production from healthy control alveolar macrophages. These studies are the first to demonstrate that circulating monocytes and alveolar macrophages from PAP patients are able to synthesize GM-CSF and respond to GM-CSF, suggesting no intrinsic abnormalities in GM-CSF signaling. In addition, these observations suggest that PAP in a subset of patients is the result of decreased availability of GM-CSF due to GM-CSF blocking activity and reduced GM-CSF production by IL-10.

Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor.

Idiopathic pulmonary alveolar proteinosis (I-PAP) is a rare disease of unknown etiology in which the alveoli fill with lipoproteinaceous material. We report here that I-PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against granulocyte/macrophage colony-stimulating factor (GM-CSF). The antibody was found to be present in all specimens of bronchoalveolar lavage fluid obtained from 11 I-PAP patients but not in samples from 2 secondary PAP patients, 53 normal subjects, and 14 patients with other lung diseases. It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro. The antibody was also found in sera from all I-PAP patients examined but not in sera from a secondary PAP patient or normal subjects, indicating that it exists systemically in I-PAP patients. As lack of GM-CSF signaling causes PAP in congenital cases and PAP-like disease in murine models, our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance.