RARE DISEASE
Hereditary pulmonary alveolar proteinosis
Hereditary pulmonary alveolar proteinosis
Hereditary pulmonary alveolar proteinosis
Synonyms: Congenital PAP, Congenital pulmonary alveolar proteinosis
Synonyms: Congenital PAP, Congenital pulmonary alveolar proteinosis
Synonyms: Congenital PAP, Congenital pulmonary alveolar proteinosis
Drug discovery
0
drugs
With orphan designations
Overview
Hereditary pulmonary alveolar proteinosis (hPAP) is a rare genetic interstitial lung disease caused by mutations in CSF2RA or CSF2RB, disrupting GM-CSF receptor signaling and impairing alveolar macrophage surfactant clearance. It presents insidiously with dyspnea, hypoxemia, and cough, often in childhood. Diagnosis relies on genetic testing, bronchoalveolar lavage showing PAS-positive material, and absence of GM-CSF autoantibodies. Whole-lung lavage (WLL) remains the primary treatment, though emerging gene therapies show promise [1][3][8][10].
Categories: rare genetic diseases, rare immunological diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
109 drug discovery papers about Hereditary pulmonary alveolar proteinosis, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
109 drug discovery papers about Hereditary pulmonary alveolar proteinosis, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2025-05-28 | Evaluating the Use of iPSC-Derived Models in Understanding the Pathogenesis of Childhood Interstitial Lung Disease.
Genetic testing has significantly improved the diagnosis of childhood interstitial lung diseases (chILD), which have long challenged clinicians due to their heterogeneity and poor characterization. It is now imperative to study variants of unknown significance (VUS) to identify pathogenic mutations to optimize diagnosis and screening in patients. Furthermore, the limited treatment options for patients with chILD worsen patient outcomes. Induced pluripotent stem cell (iPSC)-derived models could be a tool to understand the effect of novel VUS and discover new therapeutic interventions. This review seeks to evaluate the fidelity of iPSC-derived models to recapitulate the pathogenic processes of chILD and test therapeutic interventions. This paper performs a systematic search over three databases to identify iPSC-derived models studying disease-causing mutations in pediatric patients with chILD and Hermansky-Pudlak Syndrome. Of the 1452 papers initially reviewed, eight papers met the inclusion criteria using iPSC-derived models to study genetic variants. The diseases covered included common manifestations of chILDs such as surfactant protein deficiencies and hereditary pulmonary alveolar proteinosis, as well as fibrotic disorders like Hermansky-Pudlak Syndrome. These models recapitulated patient histology and key pathogenic features reported in the literature, delivering mechanistic insights into these conditions. Some papers also explored the efficacy of novel treatments, such as gene therapy. iPSC-derived models can mimic aspects of human lung responses to provide a platform for disease modeling and therapeutic testing in chILD. There are opportunities to develop more complex multi-cellular models and for the study of a wider range of variants using these tools.
2023-08-03 | Pulmonary alveolar proteinosis - current and future therapeutical strategies.
We discuss the most recent advances in the treatment of pulmonary alveolar proteinosis (PAP), an ultra-rare syndrome. Whole lung lavage (WLL) remains the gold standard of treatment for PAP syndrome. For the autoimmune form, recent trials with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) confirmed the efficacy in up to 70% of cases, especially under continuous administration. In patients with hereditary PAP with underlying GM-CSF receptor mutations, ex vivo autologous hematopoietic stem-cell gene therapy and transplantation of autologous ex vivo gene-corrected macrophages directly into the lungs are promising approaches. There are no drugs approved for PAP at present, but cause-based treatments such as GM-CSF augmentation and pulmonary macrophage transplantation are paving the way for targeted therapy for this complex syndrome.
2021-08-01 | Update on Diagnosis and Treatment of Adult Pulmonary Alveolar Proteinosis
Abstract: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary surfactant homeostasis disorder resulting in buildup of lipo-proteinaceous material within the alveoli. PAP is classified as primary (autoimmune and hereditary), secondary, congenital and unclassifiable type based on the underlying pathogenesis. PAP has an insidious onset and can, in some cases, progress to severe respiratory failure. Diagnosis is often secured with bronchoalveolar lavage in the setting of classic imaging findings. Recent insights into genetic alterations and autoimmune mechanisms have provided newer diagnostics and treatment options. In this review, we discuss the etiopathogenesis, diagnosis and treatment options available and emerging for PAP. Keywords: alveolar macrophage, surfactant protein, granulocyte macrophage-colony stimulating factor, whole lung lavage, lung transplant, gene therapy, alveolar proteinosis
2020-04-09 | The influence of genetics on therapeutic developments in pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis (PAP) is characterized by the massive accumulation of lipoproteinaceous material within alveoli, which results in progressive respiratory failure. The abnormalities in surfactant clearance are caused by defective pulmonary macrophages, whose terminal differentiation is GM-CSF-dependent. In hereditary PAP, the rupture of GM-CSF signaling is because of mutations in the GM-CSF receptor genes. This review focus on the innovative technologies of gene-correction proposed for the development of new therapeutic strategies, for hereditary PAP patients. Hematopoietic stem cell gene therapy has been successfully experimented in murine models to restore the expression of the GM-CSF receptor, however, a therapeutic approach based on bone marrow transplantation requires a preconditioning, which could be hazardous in PAP patients, who are highly susceptible to pulmonary infections. Gene-corrected pulmonary macrophages, administered directly to the lung, could represent an improved approach. Finally, patient-derived induced pluripotent stem cells seem to be promising to overcome the limited availability of primary patient cells and to generate gene-corrected macrophages, able to recover pulmonary surfactant clearance. WLL is the gold standard therapy for PAP. However, its use in hereditary PAP is limited by the difficulty of performing this technique in paediatric patients and by its purely symptomatic efficacy. The recent advances in genome engineering could provide efficacious strategies for clinical application.
2014-01-15 | Gene Correction of Human Induced Pluripotent Stem Cells Repairs the Cellular Phenotype in Pulmonary Alveolar Proteinosis
Hereditary pulmonary alveolar proteinosis (hPAP) caused by granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α-chain (CSF2RA) deficiency is a rare, life-threatening lung disease characterized by accumulation of proteins and phospholipids in the alveolar spaces. The disease is caused by a functional insufficiency of alveolar macrophages, which require GM-CSF signaling for terminal differentiation and effective degradation of alveolar proteins and phospholipids. Therapeutic options are extremely limited, and the pathophysiology underlying the defective protein degradation in hPAP alveolar macrophages remains poorly understood.To further elucidate the cellular mechanisms underlying hPAP and evaluate novel therapeutic strategies, we here investigated the potential of hPAP patient-derived induced pluripotent stem cell (PAP-iPSCs) derived monocytes and macrophages.Patient-specific PAP-iPSCs were generated from CD34(+) bone marrow cells of a CSF2RA-deficient patient with PAP. We assessed pluripotency, chromosomal integrity, and genetic correction of established iPSC lines. On hematopoietic differentiation, genetically corrected or noncorrected monocytes and macrophages were investigated in GM-CSF-dependent assays.Although monocytes and macrophages differentiated from noncorrected PAP-iPSCs exhibited distinct defects in GM-CSF-dependent functions, such as perturbed CD11b activation, phagocytic activity, and STAT5 phosphorylation after GM-CSF exposure and lack of GM-CSF uptake, these defects were fully repaired on lentiviral gene transfer of a codon-optimized CSF2RA-cDNA.These data establish PAP-iPSC-derived monocytes and macrophages as a valid in vitro disease model of CSF2RA-deficient PAP, and introduce gene-corrected iPSC-derived monocytes and macrophages as a potential autologous cell source for innovative therapeutic strategies. Transplantation of such cells to patients with hPAP could serve as a paradigmatic proof for the potential of iPSC-derived cells in clinical gene therapy.
proteins
2026-07-16 | Pulmonary Alveolar Proteinosis in Greece-Türkiye-Cyprus: Answers in a Real-Life Comparison.
Pulmonary alveolar proteinosis (PAP) is a rare disease of inappropriate alveolar surfactant accumulation. The study objective was to compare Greece-Türkiye-Cyprus cohorts, followed-up for 20 years. Data were retrieved retrospectively by chart review. One hundred and thirty patients, Greece 39, Türkiye 87, Cyprus 4, were included; 115 (89%) autoimmune (a)PAP, 13 (10%) secondary, 1 (1%) hereditary. Abnormal anti-GM-CSF antibody titre was available in 86/115 patients, further analyzed for aPAP. Forty (46%) were male, with median (IQR) age at diagnosis of 40 (31-50) years. At median (IQR) duration of clinical follow-up of 39 (18-78) months, three patients died. Non-survivors had higher rates of cardiovascular disease [67% vs. 5%, p < 0.001], LTOT (67% vs. 13%, p = 0.001), pulmonary fibrosis [67% vs. 5%] and worse functional status at follow-up [FVC% pred 49 (29) vs. 87 (74-97); p = 0.026, DLCO% pred 21 (46) vs. 72 (58-82); p = 0.016]. aPAP patients were stratified by therapy group (no WLL-no i-GM-CSF, WLL alone, i-GMCSF alone and both WLL and iGM-CSF). WLL was more frequently performed in Türkiye and i-GMCSF alone in Greece (p = 0.006). All therapies were effective. No difference was detected on outcome when sole iGM-CSF was compared to WLL alone or in combination with iGM-CSF [deceased/alive 0%/100% vs. 7%/93%, p = 0.491]. Sole iGM-CSF significantly ameliorated clinical and functional parameters of disease severity [DLCO% (p = 0.013), SatO2 (p = 0.002), 6MWT (p = 0.026)]. Across all therapy groups, pulmonary fibrosis eliminated beneficial response to treatment. This first real-life comparison of aPAP cohorts originating from three countries showed the non-inferiority of sole iGM-CSF treatment. Fibrosis negatively affects response to treatment and survival.
2025-09-27 | Pulmonary Alveolar Proteinosis: a 3-country cohort study Greece, Türkiye, Cyprus
Background: Pulmonary Alveolar Proteinosis (PAP) is a rare disease with inappropriate accumulation of surfactant in alveoli. Aim to characterize 3 cohorts in 3 Mediterranean neighbors (Greece, Türkiye, Cyprus) the last 20 years. Methods: Epidemiological, clinical and functional data were analyzed Results: Included are 124 patients: 32% Greece, 65% Türkiye, 3% Cyprus; 109 (88%) autoimmune PAP (aPAP), 13 (11%) secondary and 1 (1%) congenital; 49% male, 65% ever-smokers, followed-up 39 (16-83) months. At diagnosis median (IQR) age 39 (30-47) years, %-predicted FVC 77 (64-91), DLCO 55 (37-68),14% in LTOT. 7% had died. Whole lung lavage (WLL) in 51%, history of inhaled-GMCSF (sargramostim or molgramostim) in 44%. During FU, patients ameliorated [FVC% (p=0.007), DLCO% (p=0.001)]. Baseline characteristics of the three cohorts were similar. Significant differences were: WLL in Türkiye 64% vs 26% in Greece and Cyprus (p<0.001) and history of i-GMCSF as sole therapy 51% in Greece vs 9% in Türkiye (p<0.001). Deceased patients were more likely to be older (p=0.009), have secondary PAP (p<0.001), more comorbidities (p=0.035), higher oxygen-needs (p<0.001), worse functional status at FU (p=0.001) and complicated by pulmonary fibrosis (p<0.001). Patients who received i-GMCSF as sole therapy had no significant differences regarding age, disease severity or outcome compared to those with a history of WLL alone or in combination with i-GMCSF. Conclusion: In Türkiye WLL was the mainstay of treatment, while in Greece i-GM-CSF. Secondary PAP, age and pulmonary fibrosis negatively influenced prognosis. i-GMCSF as the sole therapy was not inferior to WLL or WLL followed by i-GMCSF irrespective of the severity of patients.
2025-01-16 | Pulmonary alveolar proteinosis: Clinical and morphological overview of a rare disease associated with macrophage dysfunction.
Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by excessive accumulation of surfactant components in alveolar macrophages, alveoli, and peripheral airways. The accumulation of surfactant is associated with only a minimal inflammatory response but can lead to the development of pulmonary fibrosis. Three clinical forms of PAP are distinguished - primary, secondary and congenital. In recent years, significant findings have helped to clarify the ethiology and pathogenesis of the disease. Apart from impaired surfactant protein function, a key role in the development of PAP is played by signal pathway of granulocyte and macrophage colonies stimulating growth factor (GM-CSF) which is necessary for the functioning of alveolar macrophages and for surfactant homeostasis. Surfactant is partially degraded by alveolar macrophages that are stimulated by GM-CSF. The role of GM-CSF has been shown especially in primary PAP, which is currently considered an autoimmune disease involving the development of GM-CSF neutralising autoantibodies. Clinically, the disease may be silent or manifest with dyspnoeic symptoms triggered by exertion and cough. However, there is a 10 to 15% rate of patients who develop respiratory failure. Total pulmonary lavage is regarded as the standard method of treatment. In addition, recombinant human GM-CSF has been studied as a prospective therapy for the treatment of PAP.
2024-12-09 | Genetic Decoding Pulmonary Alveolar Proteinosis in Children: A Case Report
Background: Nonspecific symptoms and variable clinical course are the hurdles in diagnosing pulmonary alveolar proteinosis (PAP), a rare lung disease. We report a pediatric case of hereditary PAP caused by mutations in the gene encoding granulocyte Macrophage colony-stimulating factor (GMCSF) receptor. Case Presentation: A 3 years 10-month-old female child, born to 3rd-degree consanguineous parents presented with fever, intermittent cough, and breathing difficulty ten days before hospitalization. Chest X-ray revealed bilateral diffuse alveolar infiltrates; Computed tomography (CT) showed diffuse interstitial thickening along with a crazy pavement pattern. Bronchoscopy and broncho-alveolar lavage (BAL) was performed. PAP was confirmed with BAL and genetic testing. Serum GM-CSF autoantibody test was normal but serum GM-CSF concentration was high (115.7 pg/mL). There was a continuous heterozygous deletion encompassing exon region 13 of the SLC34A2 gene, suggestive of pulmonary alveolar microlithiasis. The patient received steroids (x2 weeks), inhalers (bronchodilators & steroids), and intermittent home oxygen therapy (x2 weeks) with a good response. Discussion: Due to nonspecific symptomatology, and variation in disease severity, diagnosis of PAP is delayed or missed. Crazy paving on CT, milky fluid on BAL with similar histological features of foamy macrophages, and PAS-positive amorphous material within the alveolus are diagnostic clues. Asymptomatic patients or those with mild symptoms are managed with supportive care, monitoring, and chest imaging; moderate to severe symptoms require whole lung lavage (WLL); GMCSF Replacement therapy, an alternative to WLL Immunomodulation therapy is also considered. Conclusion: PAP can be managed conservatively with supportive therapy with good clinical outcomes and not all patients require WLL. However, patient selection is crucial.
2024-10-28 | Clinical approach for pulmonary alveolar proteinosis in children.
In this editorial, we discuss the clinical implications of the article by Zhang et al. Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by excessive surfactant accumulation in the alveoli. It is classified into four categories: Primary, secondary, congenital, and unclassified forms. Primary PAP is caused by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signaling, which is necessary for the clearance of surfactant by alveolar macrophages. It is further divided into autoimmune PAP, caused by anti-GM-CSF antibodies blocking alveolar macrophage activation, and hereditary PAP, resulting from mutations in genes encoding GM-CSF receptors. Secondary PAP develops due to conditions affecting the number or function of alveolar macrophages, such as infections, immunodeficiency, hematological disorders, or exposure to inhaled toxins. Congenital PAP is linked to mutations in genes involved in surfactant protein production. Notably, the causes of PAP differ between children and adults. Diagnostic features include a characteristic "crazy-paving" pattern on high-resolution computed tomography, accompanied by diffuse ground-glass opacities and interlobular septal thickening. The presence of PAP can be identified by the milky appearance of bronchoalveolar lavage fluid and histological evaluation. However, these methods cannot definitively determine the cause of PAP. Whole lung lavage remains the standard treatment, often combined with specific therapies based on the underlying cause.
cell therapies
2026-07-10 | Lung Transplantation for Pulmonary Alveolar Proteinosis - a Retrospective International Multi-Center Analysis.
Pulmonary alveolar proteinosis (PAP) is a rare disease. Only a small number of case reports describing lung transplantation (LTx) as a treatment option for PAP have been published. Due to this limited evidence, current guidelines on LTx for PAP remain vague. To address this gap, we collected cases of LTx for PAP worldwide. 214 centers were approached to contribute any cases of LTx performed for PAP. Re-transplantations and multi-organ transplantations were excluded. Patients were divided into two groups based on the presence of PAP recurrence after LTx. Time-to-event-analyses were performed by Kaplan-Meier curves and cox-proportional-hazards-modelling was performed with PAP recurrence as a time-dependent covariate. At a response rate of 64%, 31 centers contributed 63 patients. Most had primary PAP (n=20; 39.2%). 6 patients with secondary PAP were identified (11.8%), while 7 (13.7%) had congenital and 18 (35.3%) unclassified PAP. Etiology was not specified in 12. Patients underwent transplantation at a median 11 years (IQR 3-17) after initial diagnosis. Nine patients (15%) developed PAP recurrence after LTx. No significant difference was found regarding patient characteristics between the patients with versus without recurrence. Freedom from recurrence was 96.2% (1y), 83.5% (5y) and 70.1% (10y) post-LTx. PAP recurrence as time-dependent covariate was not significantly associated with graft loss (HR=1.88, 95%CI:0.51-6.91, p=0.342) in a cox-proportional-hazards-model. LTx provides excellent perioperative and long-term outcomes for patients with end-stage PAP and should be recommended in treatment guidelines. Although recurrence of PAP occurs in approximately 15% of cases, overall survival appeared unaffected in our limited dataset.
2026-06-01 | B95-10 A First-in-human Study of Pulmonary Macrophage Transplantation Therapy of Hereditary Pulmonary Alveolar Proteinosis
Abstract Background CSF2RA mutations cause hereditary alveolar proteinosis (hPAP), a surfactant accumulation disorder, by disrupting GM-CSF signaling to alveolar macrophages (AMs), which require GM-CSF to maintain normal surfactant clearance and other functions and regulation of AM population size (in mice). Pulmonary macrophage transplantation (PMT) is a promising therapeutic approach for hPAP based on genetically restoring GM-CSF signaling to AMs. Preclinical mouse studies demonstrated PMT was safe and that efficacy was proportional to cell dose and time allowed for treatment development. Objectives: This study evaluated the feasibility, tolerability, safety, and efficacy of CSF2RA gene/PMT therapy in a 22-year-old woman with hPAP caused by biallelic CSF2RA mutations (G174R, gene deletion). Methods Autologous, gene-corrected macrophages (cells) were prepared from bone marrow progenitors by transduction with a self-inactivating, 3rd generation lentiviral vector expressing a CSF2RA transgene, followed by ex vivo cell expansion, differentiation into macrophages, and cryopreservation until administration. The cell dose (11 million cells/kg ideal body weight) was based on mouse toxicology results and was equivalent in size to 16% of the adult human AM population. Cells were thawed, formulated in saline, tested, and instilled bronchoscopically into individual lung segments in two doses. The first was a split-dose delivered into 1, 4, then 14 segments sequentially at 2-month intervals. The second dose involved delivery into all 19 segments 16 months later. The rationale for this administration scheme was our focus on safety and because the achievable gene-correction rate had been 100% in mouse cells but only ∼50% in human cells. Results Two separate cell lots comprised 131% and 104% of the targeted production amount and met all lot-release criteria. Administration was nominal and not accompanied by bronchospasm, serious adverse events, or antibody responses to either the vector or transgene product. Evidence of biological efficacy included detection of vector DNA and transgene product in AMs, reduced bronchoalveolar lavage turbidity, and detection of morphologically normal AMs. Evidence of clinical efficacy included improvement in body mass index, DLCO%, exercise capacity, minor improvement in computed tomography, and reduction in surfactant burden (total pulmonary surfactant level) as demonstrated by time-dependent reduction in the ‘barrier signal’ from hyperpolarized 129Xe magnetic resonance imaging (MRI) (Figure). Conclusions Results show PMT therapy of hPAP was feasible, tolerable, safe, and efficacious. Clinical efficacy was proportional to cell dose and treatment duration and developed over 26 months of follow-up. Interestingly, hyperpolarized 129Xe MRI imaging was more sensitive in measuring surfactant burden than computed tomography. This abstract is funded by: NIH R33 HL156888
2024-12-02 | Restitutio ad integrum: Rescuing the Alveolar Macrophage Function with HSCT in Pulmonary Alveolar Proteinosis Due to CSF2Rα Deficiency.
Hereditary pulmonary alveolar proteinosis (hPAP) is a rare lung-related primary immunodeficiency. In hPAP, variants of genes encoding the heterodimeric GM-CSF receptor alpha or beta-chains (CSF2Rα, CSF2Rβ) lead to perturbations in GM-CSF signalling. These perturbations impair the scavenging function of pulmonary alveolar macrophages leading to accumulation of surfactant proteins and lipids within the alveoli. The replacement of defective pulmonary alveolar macrophages can be achieved with allogeneic hematopoietic stem cell transplantation. However, previous reports highlight undesirable pulmonary outcomes associated with this therapeutic approach. We report a 4-year-old developmentally normal girl born of second-degree consanguineous marriage diagnosed with severe form of CSFRα-deficient PAP. She required recurrent whole lung lavage and hence was treated with allogeneic hematopoietic stem cell transplantation. A reduced toxicity treosulfan-based myeloablative regimen with alemtuzumab serotherapy was used for conditioning. Ciclosporin, mycophenolate mofetil and FAM (fluticasone inhaler, azithromycin, montelukast) were used to prevent graft-versus-host disease and immune-related complications of lung. Her post-transplant course was uneventful with full donor chimerism and complete resolution of symptoms. We demonstrate for the first time in a case of severe CSF2Rα-deficient PAP, the successful use of hematopoietic stem cell transplantation as a primary curative treatment, restoring normal lungs both anatomically and functionally. The case report provides evidence for considering allogeneic hematopoietic stem cell transplant in severe forms of CSF2R-deficient PAP.
2024-04-10 | A toxicology study of Csf2ra complementation and pulmonary macrophage transplantation therapy of hereditary PAP in mice.
Pulmonary macrophage transplantation (PMT) is a gene and cell transplantation approach in development as therapy for hereditary pulmonary alveolar proteinosis (hPAP), a surfactant accumulation disorder caused by mutations in CSF2RA/B (and murine homologs). We conducted a toxicology study of PMT of Csf2ra gene-corrected macrophages (mGM-Rα+Mϕs) or saline-control intervention in Csf2raKO or wild-type (WT) mice including single ascending dose and repeat ascending dose studies evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. Lentiviral-mediated Csf2ra cDNA transfer restored GM-CSF signaling in mGM-Rα+Mϕs. Following PMT, mGM-Rα+Mϕs engrafted, remained within the lungs, and did not undergo uncontrolled proliferation or result in bronchospasm, pulmonary function abnormalities, pulmonary or systemic inflammation, anti-transgene product antibodies, or pulmonary fibrosis. Aggressive male fighting caused a similarly low rate of serious adverse events in saline- and PMT-treated mice. Transient, minor pulmonary neutrophilia and exacerbation of pre-existing hPAP-related lymphocytosis were observed 14 days after PMT of the safety margin dose but not the target dose (5,000,000 or 500,000 mGM-Rα+Mϕs, respectively) and only in Csf2raKO mice but not in WT mice. PMT reduced lung disease severity in Csf2raKO mice. Results indicate PMT of mGM-Rα+Mϕs was safe, well tolerated, and therapeutically efficacious in Csf2raKO mice, and established a no adverse effect level and 10-fold safety margin.
2023-09-09 | Preclinical studies supporting a first-in-human trial of pulmonary macrophage transplantation therapy of CSF2RA-associaited PAP
CSF2RA mutations cause hereditary pulmonary alveolar proteinosis (hPAP), a disorder of alveolar macrophage dysfunction, surfactant accumulation, and hypoxemic respiratory failure, and, in some patients, serious infections or pulmonary fibrosis - without an approved disease-specific therapy. After reporting hPAP in 2008, we developed diagnostics, identified a patient cohort, and defined its pathogenesis, presentation, and natural history. We discovered that lentiviral-mediated CSF2RA gene transfer restored GM-CSF signaling in hPAP patient macrophages. We developed and validated Csf2raKO mice as a model of hPAP and found pulmonary macrophage transplantation (PMT) corrected hPAP and normalized disease-related biomarkers. After reaching an agreement with the US FDA, a formal toxicology study demonstrated that PMT was safe, defined the cell dose-clinical benefit response relationship, and established a no adverse effects level (NOAEL), minimum effective dose, and maximum safe dose. In addition, we developed novel methods for manufacturing and certificating clinical grade, autologous CD34+ cell-derived, lentiviral vector-mediated CSF2RA gene-corrected macrophages under good manufacturing practice (GMP)-compliant conditions in our institutional GMP manufacturing facility. A macrophage cell product-delivery device compatibility study established the accuracy, viability, potency, composition, and sterility of delivering gene-corrected macrophages using a video-bronchoscope. Our investigational new drug application (IND 28593) and human clinical trial were approved by the FDA and our institutional review board and the clinical trial is scheduled to begin in 2023.
small molecules
2025-12-11 | Successful methionine treatment for diffuse lung disease in a child with pathogenic MARS-1 gene variants
Introduction Variants in the MARS- 1 gene lead to heterogeneous multisystem disorders involving the lungs, liver, hematopoietic system, immune system, and central nervous system (La Fay C et al., Eur J Med Genet 2021; 64(11): 104334). MARS-1 -associated pulmonary disorders have so far been described as diffuse lung disease, which can present in various entities. One of these is pulmonary alveolar proteinosis (PAP), a rare disease characterized by the accumulation of a surfactant in the alveoli. While treatment options for hereditary PAP currently include whole lung lavage, bone marrow transplantation, or lung transplantation, recent case series have shown that L-Methionine supplementation can lead to disease recovery in patients with MARS-1 variants. This case report describes treatment with L-methionine supplementation in a patient with compound heterozygous pathogenic variants in MARS-1 , who did not suffer from PAP but from childhood interstitial lung disease as part of a multisystem involvement and who experienced a remarkable and rapid clinical and radiological improvement. Publication History Received: 21 August 2025 Accepted: 11 November 2025 Article published online: 11 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2024-07-17 | Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.
Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.
2024-01-22 | [Lung involvement in autoinflammatory diseases].
Genetic autoinflammatory diseases are now a recognized and rapidly expanding group. The lung involvement historically associated with autoinflammatory diseases is inflammatory seritis, primarily seen in familial Mediterranean fever and other interleukin-1 mediated diseases. Over the last ten years, pulmonary involvement has been the core presentation of two autoinflammatory diseases associated with constitutive type I interferon activation, i.e. SAVI and COPA syndrome. Most patients with these diseases usually develop early progression to pulmonary fibrosis, which is responsible for high rates of morbidity and mortality. Other rare autoinflammatory diseases are associated with alveolar proteinosis, particularly when related to MARS mutations. Additionally, in adults, VEXAS is frequently associated with pulmonary involvement, albeit without prognosis effect. A molecular approach to autoinflammatory diseases enables not only the definition of biomarkers for diagnosis, but also the identification of targeted treatments. Examples include JAK inhibitors in SAVI and COPA syndrome, even though this therapy does not prevent progression to pulmonary fibrosis. Another illustrative example is the efficacy of methionine supplementation in alveolar proteinosis linked to MARS mutations. Overall, in autoinflammatory diseases the lung is now emerging as a possible affected organ. Continuing discovery of new autoinflammatory diseases is likely to uncover further pathologies involving the lung. Such advances are expected to lead to the development of novel therapeutic perspectives.
2022-02-22 | Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency.
Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.
2020-09-08 | Pharmacotherapy options in pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis (PAP) is a heterogeneous group of rare diseases characterized by the abnormal production and impaired degradation of pulmonary surfactant as a result of malfunctioning of alveolar macrophages. This is due to the downstream dysregulation of the GM-CSF pathway, which can be caused by specific autoantibodies (autoimmune, aPAP formerly known as idiopathic iPAP), direct injury to alveolar macrophages (e.g. by toxic inhaled agents.), or by genetic defects (hereditary or congenital PAP). Few pharmacotherapy options are currently available to treat this disease. The authors discuss the exogenous administration of GM-CSF, rituximab, and the potential role of cholesterol lowering medications in this review. The authors, furthermore, provide their opinion on the available pharmacotherapeutic options and give their future perspectives. Inhaled GM-CSF remains the most commonly used therapy in patients with iPAP but other inhaled therapies such as PPARγ activators should be considered, especially in patients who are partially responsive or unresponsive to traditional treatments.
other
2023-06-14 | Alveolar macrophages in pulmonary alveolar proteinosis: origin, function, and therapeutic strategies
Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar macrophages (AMs) have been identified as playing a pivotal role in the pathogenesis of PAP. In most of PAP cases, the disease is triggered by impaired cholesterol clearance in AMs that depend on granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in defective alveolar surfactant clearance and disruption of pulmonary homeostasis. Currently, novel pathogenesis-based therapies are being developed that target the GM-CSF signaling, cholesterol homeostasis, and immune modulation of AMs. In this review, we summarize the origin and functional role of AMs in PAP, as well as the latest therapeutic strategies aimed at addressing this disease. Our goal is to provide new perspectives and insights into the pathogenesis of PAP, and thereby identify promising new treatments for this disease.
2017-09-16 | Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis
Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN-γ released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP. Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN-γ released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP.
2009-10-01 | Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages
Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of pulmonary surfactant, respiratory insufficiency, and increased infections. It occurs in various clinical settings that disrupt surfactant catabolism in alveolar macrophages, including a relatively more common autoimmune disease caused by GM-CSF autoantibodies and a rare congenital disease caused by CSF2RA mutations. Recent results demonstrate that GM-CSF is crucial for alveolar macrophage terminal differentiation and immune functions, pulmonary surfactant homeostasis, and lung host defense. GM-CSF is also required to determine the basal functional capacity of circulating neutrophils, including adhesion, phagocytosis, and microbial killing. PAP research has illuminated the crucial role of GM-CSF in innate immunity and led to novel therapy for PAP and the potential use of anti-GM-CSF therapy in other common disorders.
2006-01-12 | Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration
Abstract: 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.
1997-12-01 | GM-CSF Gene Expression Is Normal but Protein Release Is Absent in a Patient with Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by an excessive accumulation of surfactant lipids and proteins in the alveolar space. In mice with a homozygous deletion of granulocyte macrophage-colony stimulating factor (GM-CSF), their phenotype mimics PAP. To evaluate whether the knockout mouse model mimics human disease, we evaluated GM-CSF expression in alveolar macrophages from a patient with PAP. We performed multiple whole lung lavages on a patient with PAP, and cultured BAL cells in the presence or absence of LPS. In contrast to the GM-CSF knockout mouse, human BAL cells from a patient with PAP expressed mRNA for GM-CSF following LPS stimulation. However, similar to the knockout mouse, GM-CSF protein release from BAL cells was undetectable with or without LPS. BAL cells from normal human controls released GM-CSF in abundance after LPS stimulation. In BAL cells from the patient with PAP, neutralization of interleukin-10 (IL-10) by anti-IL-10 antibody, resulted in enhanced GM-CSF production. Thus, alveolar macrophages from a PAP lung have deficient GM-CSF production analogous to the GM-CSF knockout mice; in contrast, human cells from a PAP lung have an intact GM-CSF gene. This case report illustrates an important difference between the knockout mouse model of PAP and the human disease. Tchou-Wong K-M, Harkin TJ, Chi C, Bodkin M, Rom WN. GM-CSF gene expression is normal but protein release is absent in a patient with pulmonary alveolar proteinosis.
gene therapies
2025-05-28 | Evaluating the Use of iPSC-Derived Models in Understanding the Pathogenesis of Childhood Interstitial Lung Disease.
Genetic testing has significantly improved the diagnosis of childhood interstitial lung diseases (chILD), which have long challenged clinicians due to their heterogeneity and poor characterization. It is now imperative to study variants of unknown significance (VUS) to identify pathogenic mutations to optimize diagnosis and screening in patients. Furthermore, the limited treatment options for patients with chILD worsen patient outcomes. Induced pluripotent stem cell (iPSC)-derived models could be a tool to understand the effect of novel VUS and discover new therapeutic interventions. This review seeks to evaluate the fidelity of iPSC-derived models to recapitulate the pathogenic processes of chILD and test therapeutic interventions. This paper performs a systematic search over three databases to identify iPSC-derived models studying disease-causing mutations in pediatric patients with chILD and Hermansky-Pudlak Syndrome. Of the 1452 papers initially reviewed, eight papers met the inclusion criteria using iPSC-derived models to study genetic variants. The diseases covered included common manifestations of chILDs such as surfactant protein deficiencies and hereditary pulmonary alveolar proteinosis, as well as fibrotic disorders like Hermansky-Pudlak Syndrome. These models recapitulated patient histology and key pathogenic features reported in the literature, delivering mechanistic insights into these conditions. Some papers also explored the efficacy of novel treatments, such as gene therapy. iPSC-derived models can mimic aspects of human lung responses to provide a platform for disease modeling and therapeutic testing in chILD. There are opportunities to develop more complex multi-cellular models and for the study of a wider range of variants using these tools.
2023-08-03 | Pulmonary alveolar proteinosis - current and future therapeutical strategies.
We discuss the most recent advances in the treatment of pulmonary alveolar proteinosis (PAP), an ultra-rare syndrome. Whole lung lavage (WLL) remains the gold standard of treatment for PAP syndrome. For the autoimmune form, recent trials with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) confirmed the efficacy in up to 70% of cases, especially under continuous administration. In patients with hereditary PAP with underlying GM-CSF receptor mutations, ex vivo autologous hematopoietic stem-cell gene therapy and transplantation of autologous ex vivo gene-corrected macrophages directly into the lungs are promising approaches. There are no drugs approved for PAP at present, but cause-based treatments such as GM-CSF augmentation and pulmonary macrophage transplantation are paving the way for targeted therapy for this complex syndrome.
2021-08-01 | Update on Diagnosis and Treatment of Adult Pulmonary Alveolar Proteinosis
Abstract: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary surfactant homeostasis disorder resulting in buildup of lipo-proteinaceous material within the alveoli. PAP is classified as primary (autoimmune and hereditary), secondary, congenital and unclassifiable type based on the underlying pathogenesis. PAP has an insidious onset and can, in some cases, progress to severe respiratory failure. Diagnosis is often secured with bronchoalveolar lavage in the setting of classic imaging findings. Recent insights into genetic alterations and autoimmune mechanisms have provided newer diagnostics and treatment options. In this review, we discuss the etiopathogenesis, diagnosis and treatment options available and emerging for PAP. Keywords: alveolar macrophage, surfactant protein, granulocyte macrophage-colony stimulating factor, whole lung lavage, lung transplant, gene therapy, alveolar proteinosis
2020-04-09 | The influence of genetics on therapeutic developments in pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis (PAP) is characterized by the massive accumulation of lipoproteinaceous material within alveoli, which results in progressive respiratory failure. The abnormalities in surfactant clearance are caused by defective pulmonary macrophages, whose terminal differentiation is GM-CSF-dependent. In hereditary PAP, the rupture of GM-CSF signaling is because of mutations in the GM-CSF receptor genes. This review focus on the innovative technologies of gene-correction proposed for the development of new therapeutic strategies, for hereditary PAP patients. Hematopoietic stem cell gene therapy has been successfully experimented in murine models to restore the expression of the GM-CSF receptor, however, a therapeutic approach based on bone marrow transplantation requires a preconditioning, which could be hazardous in PAP patients, who are highly susceptible to pulmonary infections. Gene-corrected pulmonary macrophages, administered directly to the lung, could represent an improved approach. Finally, patient-derived induced pluripotent stem cells seem to be promising to overcome the limited availability of primary patient cells and to generate gene-corrected macrophages, able to recover pulmonary surfactant clearance. WLL is the gold standard therapy for PAP. However, its use in hereditary PAP is limited by the difficulty of performing this technique in paediatric patients and by its purely symptomatic efficacy. The recent advances in genome engineering could provide efficacious strategies for clinical application.
2014-01-15 | Gene Correction of Human Induced Pluripotent Stem Cells Repairs the Cellular Phenotype in Pulmonary Alveolar Proteinosis
Hereditary pulmonary alveolar proteinosis (hPAP) caused by granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α-chain (CSF2RA) deficiency is a rare, life-threatening lung disease characterized by accumulation of proteins and phospholipids in the alveolar spaces. The disease is caused by a functional insufficiency of alveolar macrophages, which require GM-CSF signaling for terminal differentiation and effective degradation of alveolar proteins and phospholipids. Therapeutic options are extremely limited, and the pathophysiology underlying the defective protein degradation in hPAP alveolar macrophages remains poorly understood.To further elucidate the cellular mechanisms underlying hPAP and evaluate novel therapeutic strategies, we here investigated the potential of hPAP patient-derived induced pluripotent stem cell (PAP-iPSCs) derived monocytes and macrophages.Patient-specific PAP-iPSCs were generated from CD34(+) bone marrow cells of a CSF2RA-deficient patient with PAP. We assessed pluripotency, chromosomal integrity, and genetic correction of established iPSC lines. On hematopoietic differentiation, genetically corrected or noncorrected monocytes and macrophages were investigated in GM-CSF-dependent assays.Although monocytes and macrophages differentiated from noncorrected PAP-iPSCs exhibited distinct defects in GM-CSF-dependent functions, such as perturbed CD11b activation, phagocytic activity, and STAT5 phosphorylation after GM-CSF exposure and lack of GM-CSF uptake, these defects were fully repaired on lentiviral gene transfer of a codon-optimized CSF2RA-cDNA.These data establish PAP-iPSC-derived monocytes and macrophages as a valid in vitro disease model of CSF2RA-deficient PAP, and introduce gene-corrected iPSC-derived monocytes and macrophages as a potential autologous cell source for innovative therapeutic strategies. Transplantation of such cells to patients with hPAP could serve as a paradigmatic proof for the potential of iPSC-derived cells in clinical gene therapy.
proteins
2026-07-16 | Pulmonary Alveolar Proteinosis in Greece-Türkiye-Cyprus: Answers in a Real-Life Comparison.
Pulmonary alveolar proteinosis (PAP) is a rare disease of inappropriate alveolar surfactant accumulation. The study objective was to compare Greece-Türkiye-Cyprus cohorts, followed-up for 20 years. Data were retrieved retrospectively by chart review. One hundred and thirty patients, Greece 39, Türkiye 87, Cyprus 4, were included; 115 (89%) autoimmune (a)PAP, 13 (10%) secondary, 1 (1%) hereditary. Abnormal anti-GM-CSF antibody titre was available in 86/115 patients, further analyzed for aPAP. Forty (46%) were male, with median (IQR) age at diagnosis of 40 (31-50) years. At median (IQR) duration of clinical follow-up of 39 (18-78) months, three patients died. Non-survivors had higher rates of cardiovascular disease [67% vs. 5%, p < 0.001], LTOT (67% vs. 13%, p = 0.001), pulmonary fibrosis [67% vs. 5%] and worse functional status at follow-up [FVC% pred 49 (29) vs. 87 (74-97); p = 0.026, DLCO% pred 21 (46) vs. 72 (58-82); p = 0.016]. aPAP patients were stratified by therapy group (no WLL-no i-GM-CSF, WLL alone, i-GMCSF alone and both WLL and iGM-CSF). WLL was more frequently performed in Türkiye and i-GMCSF alone in Greece (p = 0.006). All therapies were effective. No difference was detected on outcome when sole iGM-CSF was compared to WLL alone or in combination with iGM-CSF [deceased/alive 0%/100% vs. 7%/93%, p = 0.491]. Sole iGM-CSF significantly ameliorated clinical and functional parameters of disease severity [DLCO% (p = 0.013), SatO2 (p = 0.002), 6MWT (p = 0.026)]. Across all therapy groups, pulmonary fibrosis eliminated beneficial response to treatment. This first real-life comparison of aPAP cohorts originating from three countries showed the non-inferiority of sole iGM-CSF treatment. Fibrosis negatively affects response to treatment and survival.
2025-09-27 | Pulmonary Alveolar Proteinosis: a 3-country cohort study Greece, Türkiye, Cyprus
Background: Pulmonary Alveolar Proteinosis (PAP) is a rare disease with inappropriate accumulation of surfactant in alveoli. Aim to characterize 3 cohorts in 3 Mediterranean neighbors (Greece, Türkiye, Cyprus) the last 20 years. Methods: Epidemiological, clinical and functional data were analyzed Results: Included are 124 patients: 32% Greece, 65% Türkiye, 3% Cyprus; 109 (88%) autoimmune PAP (aPAP), 13 (11%) secondary and 1 (1%) congenital; 49% male, 65% ever-smokers, followed-up 39 (16-83) months. At diagnosis median (IQR) age 39 (30-47) years, %-predicted FVC 77 (64-91), DLCO 55 (37-68),14% in LTOT. 7% had died. Whole lung lavage (WLL) in 51%, history of inhaled-GMCSF (sargramostim or molgramostim) in 44%. During FU, patients ameliorated [FVC% (p=0.007), DLCO% (p=0.001)]. Baseline characteristics of the three cohorts were similar. Significant differences were: WLL in Türkiye 64% vs 26% in Greece and Cyprus (p<0.001) and history of i-GMCSF as sole therapy 51% in Greece vs 9% in Türkiye (p<0.001). Deceased patients were more likely to be older (p=0.009), have secondary PAP (p<0.001), more comorbidities (p=0.035), higher oxygen-needs (p<0.001), worse functional status at FU (p=0.001) and complicated by pulmonary fibrosis (p<0.001). Patients who received i-GMCSF as sole therapy had no significant differences regarding age, disease severity or outcome compared to those with a history of WLL alone or in combination with i-GMCSF. Conclusion: In Türkiye WLL was the mainstay of treatment, while in Greece i-GM-CSF. Secondary PAP, age and pulmonary fibrosis negatively influenced prognosis. i-GMCSF as the sole therapy was not inferior to WLL or WLL followed by i-GMCSF irrespective of the severity of patients.
2025-01-16 | Pulmonary alveolar proteinosis: Clinical and morphological overview of a rare disease associated with macrophage dysfunction.
Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by excessive accumulation of surfactant components in alveolar macrophages, alveoli, and peripheral airways. The accumulation of surfactant is associated with only a minimal inflammatory response but can lead to the development of pulmonary fibrosis. Three clinical forms of PAP are distinguished - primary, secondary and congenital. In recent years, significant findings have helped to clarify the ethiology and pathogenesis of the disease. Apart from impaired surfactant protein function, a key role in the development of PAP is played by signal pathway of granulocyte and macrophage colonies stimulating growth factor (GM-CSF) which is necessary for the functioning of alveolar macrophages and for surfactant homeostasis. Surfactant is partially degraded by alveolar macrophages that are stimulated by GM-CSF. The role of GM-CSF has been shown especially in primary PAP, which is currently considered an autoimmune disease involving the development of GM-CSF neutralising autoantibodies. Clinically, the disease may be silent or manifest with dyspnoeic symptoms triggered by exertion and cough. However, there is a 10 to 15% rate of patients who develop respiratory failure. Total pulmonary lavage is regarded as the standard method of treatment. In addition, recombinant human GM-CSF has been studied as a prospective therapy for the treatment of PAP.
2024-12-09 | Genetic Decoding Pulmonary Alveolar Proteinosis in Children: A Case Report
Background: Nonspecific symptoms and variable clinical course are the hurdles in diagnosing pulmonary alveolar proteinosis (PAP), a rare lung disease. We report a pediatric case of hereditary PAP caused by mutations in the gene encoding granulocyte Macrophage colony-stimulating factor (GMCSF) receptor. Case Presentation: A 3 years 10-month-old female child, born to 3rd-degree consanguineous parents presented with fever, intermittent cough, and breathing difficulty ten days before hospitalization. Chest X-ray revealed bilateral diffuse alveolar infiltrates; Computed tomography (CT) showed diffuse interstitial thickening along with a crazy pavement pattern. Bronchoscopy and broncho-alveolar lavage (BAL) was performed. PAP was confirmed with BAL and genetic testing. Serum GM-CSF autoantibody test was normal but serum GM-CSF concentration was high (115.7 pg/mL). There was a continuous heterozygous deletion encompassing exon region 13 of the SLC34A2 gene, suggestive of pulmonary alveolar microlithiasis. The patient received steroids (x2 weeks), inhalers (bronchodilators & steroids), and intermittent home oxygen therapy (x2 weeks) with a good response. Discussion: Due to nonspecific symptomatology, and variation in disease severity, diagnosis of PAP is delayed or missed. Crazy paving on CT, milky fluid on BAL with similar histological features of foamy macrophages, and PAS-positive amorphous material within the alveolus are diagnostic clues. Asymptomatic patients or those with mild symptoms are managed with supportive care, monitoring, and chest imaging; moderate to severe symptoms require whole lung lavage (WLL); GMCSF Replacement therapy, an alternative to WLL Immunomodulation therapy is also considered. Conclusion: PAP can be managed conservatively with supportive therapy with good clinical outcomes and not all patients require WLL. However, patient selection is crucial.
2024-10-28 | Clinical approach for pulmonary alveolar proteinosis in children.
In this editorial, we discuss the clinical implications of the article by Zhang et al. Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by excessive surfactant accumulation in the alveoli. It is classified into four categories: Primary, secondary, congenital, and unclassified forms. Primary PAP is caused by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signaling, which is necessary for the clearance of surfactant by alveolar macrophages. It is further divided into autoimmune PAP, caused by anti-GM-CSF antibodies blocking alveolar macrophage activation, and hereditary PAP, resulting from mutations in genes encoding GM-CSF receptors. Secondary PAP develops due to conditions affecting the number or function of alveolar macrophages, such as infections, immunodeficiency, hematological disorders, or exposure to inhaled toxins. Congenital PAP is linked to mutations in genes involved in surfactant protein production. Notably, the causes of PAP differ between children and adults. Diagnostic features include a characteristic "crazy-paving" pattern on high-resolution computed tomography, accompanied by diffuse ground-glass opacities and interlobular septal thickening. The presence of PAP can be identified by the milky appearance of bronchoalveolar lavage fluid and histological evaluation. However, these methods cannot definitively determine the cause of PAP. Whole lung lavage remains the standard treatment, often combined with specific therapies based on the underlying cause.
cell therapies
2026-07-10 | Lung Transplantation for Pulmonary Alveolar Proteinosis - a Retrospective International Multi-Center Analysis.
Pulmonary alveolar proteinosis (PAP) is a rare disease. Only a small number of case reports describing lung transplantation (LTx) as a treatment option for PAP have been published. Due to this limited evidence, current guidelines on LTx for PAP remain vague. To address this gap, we collected cases of LTx for PAP worldwide. 214 centers were approached to contribute any cases of LTx performed for PAP. Re-transplantations and multi-organ transplantations were excluded. Patients were divided into two groups based on the presence of PAP recurrence after LTx. Time-to-event-analyses were performed by Kaplan-Meier curves and cox-proportional-hazards-modelling was performed with PAP recurrence as a time-dependent covariate. At a response rate of 64%, 31 centers contributed 63 patients. Most had primary PAP (n=20; 39.2%). 6 patients with secondary PAP were identified (11.8%), while 7 (13.7%) had congenital and 18 (35.3%) unclassified PAP. Etiology was not specified in 12. Patients underwent transplantation at a median 11 years (IQR 3-17) after initial diagnosis. Nine patients (15%) developed PAP recurrence after LTx. No significant difference was found regarding patient characteristics between the patients with versus without recurrence. Freedom from recurrence was 96.2% (1y), 83.5% (5y) and 70.1% (10y) post-LTx. PAP recurrence as time-dependent covariate was not significantly associated with graft loss (HR=1.88, 95%CI:0.51-6.91, p=0.342) in a cox-proportional-hazards-model. LTx provides excellent perioperative and long-term outcomes for patients with end-stage PAP and should be recommended in treatment guidelines. Although recurrence of PAP occurs in approximately 15% of cases, overall survival appeared unaffected in our limited dataset.
2026-06-01 | B95-10 A First-in-human Study of Pulmonary Macrophage Transplantation Therapy of Hereditary Pulmonary Alveolar Proteinosis
Abstract Background CSF2RA mutations cause hereditary alveolar proteinosis (hPAP), a surfactant accumulation disorder, by disrupting GM-CSF signaling to alveolar macrophages (AMs), which require GM-CSF to maintain normal surfactant clearance and other functions and regulation of AM population size (in mice). Pulmonary macrophage transplantation (PMT) is a promising therapeutic approach for hPAP based on genetically restoring GM-CSF signaling to AMs. Preclinical mouse studies demonstrated PMT was safe and that efficacy was proportional to cell dose and time allowed for treatment development. Objectives: This study evaluated the feasibility, tolerability, safety, and efficacy of CSF2RA gene/PMT therapy in a 22-year-old woman with hPAP caused by biallelic CSF2RA mutations (G174R, gene deletion). Methods Autologous, gene-corrected macrophages (cells) were prepared from bone marrow progenitors by transduction with a self-inactivating, 3rd generation lentiviral vector expressing a CSF2RA transgene, followed by ex vivo cell expansion, differentiation into macrophages, and cryopreservation until administration. The cell dose (11 million cells/kg ideal body weight) was based on mouse toxicology results and was equivalent in size to 16% of the adult human AM population. Cells were thawed, formulated in saline, tested, and instilled bronchoscopically into individual lung segments in two doses. The first was a split-dose delivered into 1, 4, then 14 segments sequentially at 2-month intervals. The second dose involved delivery into all 19 segments 16 months later. The rationale for this administration scheme was our focus on safety and because the achievable gene-correction rate had been 100% in mouse cells but only ∼50% in human cells. Results Two separate cell lots comprised 131% and 104% of the targeted production amount and met all lot-release criteria. Administration was nominal and not accompanied by bronchospasm, serious adverse events, or antibody responses to either the vector or transgene product. Evidence of biological efficacy included detection of vector DNA and transgene product in AMs, reduced bronchoalveolar lavage turbidity, and detection of morphologically normal AMs. Evidence of clinical efficacy included improvement in body mass index, DLCO%, exercise capacity, minor improvement in computed tomography, and reduction in surfactant burden (total pulmonary surfactant level) as demonstrated by time-dependent reduction in the ‘barrier signal’ from hyperpolarized 129Xe magnetic resonance imaging (MRI) (Figure). Conclusions Results show PMT therapy of hPAP was feasible, tolerable, safe, and efficacious. Clinical efficacy was proportional to cell dose and treatment duration and developed over 26 months of follow-up. Interestingly, hyperpolarized 129Xe MRI imaging was more sensitive in measuring surfactant burden than computed tomography. This abstract is funded by: NIH R33 HL156888
2024-12-02 | Restitutio ad integrum: Rescuing the Alveolar Macrophage Function with HSCT in Pulmonary Alveolar Proteinosis Due to CSF2Rα Deficiency.
Hereditary pulmonary alveolar proteinosis (hPAP) is a rare lung-related primary immunodeficiency. In hPAP, variants of genes encoding the heterodimeric GM-CSF receptor alpha or beta-chains (CSF2Rα, CSF2Rβ) lead to perturbations in GM-CSF signalling. These perturbations impair the scavenging function of pulmonary alveolar macrophages leading to accumulation of surfactant proteins and lipids within the alveoli. The replacement of defective pulmonary alveolar macrophages can be achieved with allogeneic hematopoietic stem cell transplantation. However, previous reports highlight undesirable pulmonary outcomes associated with this therapeutic approach. We report a 4-year-old developmentally normal girl born of second-degree consanguineous marriage diagnosed with severe form of CSFRα-deficient PAP. She required recurrent whole lung lavage and hence was treated with allogeneic hematopoietic stem cell transplantation. A reduced toxicity treosulfan-based myeloablative regimen with alemtuzumab serotherapy was used for conditioning. Ciclosporin, mycophenolate mofetil and FAM (fluticasone inhaler, azithromycin, montelukast) were used to prevent graft-versus-host disease and immune-related complications of lung. Her post-transplant course was uneventful with full donor chimerism and complete resolution of symptoms. We demonstrate for the first time in a case of severe CSF2Rα-deficient PAP, the successful use of hematopoietic stem cell transplantation as a primary curative treatment, restoring normal lungs both anatomically and functionally. The case report provides evidence for considering allogeneic hematopoietic stem cell transplant in severe forms of CSF2R-deficient PAP.
2024-04-10 | A toxicology study of Csf2ra complementation and pulmonary macrophage transplantation therapy of hereditary PAP in mice.
Pulmonary macrophage transplantation (PMT) is a gene and cell transplantation approach in development as therapy for hereditary pulmonary alveolar proteinosis (hPAP), a surfactant accumulation disorder caused by mutations in CSF2RA/B (and murine homologs). We conducted a toxicology study of PMT of Csf2ra gene-corrected macrophages (mGM-Rα+Mϕs) or saline-control intervention in Csf2raKO or wild-type (WT) mice including single ascending dose and repeat ascending dose studies evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. Lentiviral-mediated Csf2ra cDNA transfer restored GM-CSF signaling in mGM-Rα+Mϕs. Following PMT, mGM-Rα+Mϕs engrafted, remained within the lungs, and did not undergo uncontrolled proliferation or result in bronchospasm, pulmonary function abnormalities, pulmonary or systemic inflammation, anti-transgene product antibodies, or pulmonary fibrosis. Aggressive male fighting caused a similarly low rate of serious adverse events in saline- and PMT-treated mice. Transient, minor pulmonary neutrophilia and exacerbation of pre-existing hPAP-related lymphocytosis were observed 14 days after PMT of the safety margin dose but not the target dose (5,000,000 or 500,000 mGM-Rα+Mϕs, respectively) and only in Csf2raKO mice but not in WT mice. PMT reduced lung disease severity in Csf2raKO mice. Results indicate PMT of mGM-Rα+Mϕs was safe, well tolerated, and therapeutically efficacious in Csf2raKO mice, and established a no adverse effect level and 10-fold safety margin.
2023-09-09 | Preclinical studies supporting a first-in-human trial of pulmonary macrophage transplantation therapy of CSF2RA-associaited PAP
CSF2RA mutations cause hereditary pulmonary alveolar proteinosis (hPAP), a disorder of alveolar macrophage dysfunction, surfactant accumulation, and hypoxemic respiratory failure, and, in some patients, serious infections or pulmonary fibrosis - without an approved disease-specific therapy. After reporting hPAP in 2008, we developed diagnostics, identified a patient cohort, and defined its pathogenesis, presentation, and natural history. We discovered that lentiviral-mediated CSF2RA gene transfer restored GM-CSF signaling in hPAP patient macrophages. We developed and validated Csf2raKO mice as a model of hPAP and found pulmonary macrophage transplantation (PMT) corrected hPAP and normalized disease-related biomarkers. After reaching an agreement with the US FDA, a formal toxicology study demonstrated that PMT was safe, defined the cell dose-clinical benefit response relationship, and established a no adverse effects level (NOAEL), minimum effective dose, and maximum safe dose. In addition, we developed novel methods for manufacturing and certificating clinical grade, autologous CD34+ cell-derived, lentiviral vector-mediated CSF2RA gene-corrected macrophages under good manufacturing practice (GMP)-compliant conditions in our institutional GMP manufacturing facility. A macrophage cell product-delivery device compatibility study established the accuracy, viability, potency, composition, and sterility of delivering gene-corrected macrophages using a video-bronchoscope. Our investigational new drug application (IND 28593) and human clinical trial were approved by the FDA and our institutional review board and the clinical trial is scheduled to begin in 2023.
small molecules
2025-12-11 | Successful methionine treatment for diffuse lung disease in a child with pathogenic MARS-1 gene variants
Introduction Variants in the MARS- 1 gene lead to heterogeneous multisystem disorders involving the lungs, liver, hematopoietic system, immune system, and central nervous system (La Fay C et al., Eur J Med Genet 2021; 64(11): 104334). MARS-1 -associated pulmonary disorders have so far been described as diffuse lung disease, which can present in various entities. One of these is pulmonary alveolar proteinosis (PAP), a rare disease characterized by the accumulation of a surfactant in the alveoli. While treatment options for hereditary PAP currently include whole lung lavage, bone marrow transplantation, or lung transplantation, recent case series have shown that L-Methionine supplementation can lead to disease recovery in patients with MARS-1 variants. This case report describes treatment with L-methionine supplementation in a patient with compound heterozygous pathogenic variants in MARS-1 , who did not suffer from PAP but from childhood interstitial lung disease as part of a multisystem involvement and who experienced a remarkable and rapid clinical and radiological improvement. Publication History Received: 21 August 2025 Accepted: 11 November 2025 Article published online: 11 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2024-07-17 | Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.
Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.
2024-01-22 | [Lung involvement in autoinflammatory diseases].
Genetic autoinflammatory diseases are now a recognized and rapidly expanding group. The lung involvement historically associated with autoinflammatory diseases is inflammatory seritis, primarily seen in familial Mediterranean fever and other interleukin-1 mediated diseases. Over the last ten years, pulmonary involvement has been the core presentation of two autoinflammatory diseases associated with constitutive type I interferon activation, i.e. SAVI and COPA syndrome. Most patients with these diseases usually develop early progression to pulmonary fibrosis, which is responsible for high rates of morbidity and mortality. Other rare autoinflammatory diseases are associated with alveolar proteinosis, particularly when related to MARS mutations. Additionally, in adults, VEXAS is frequently associated with pulmonary involvement, albeit without prognosis effect. A molecular approach to autoinflammatory diseases enables not only the definition of biomarkers for diagnosis, but also the identification of targeted treatments. Examples include JAK inhibitors in SAVI and COPA syndrome, even though this therapy does not prevent progression to pulmonary fibrosis. Another illustrative example is the efficacy of methionine supplementation in alveolar proteinosis linked to MARS mutations. Overall, in autoinflammatory diseases the lung is now emerging as a possible affected organ. Continuing discovery of new autoinflammatory diseases is likely to uncover further pathologies involving the lung. Such advances are expected to lead to the development of novel therapeutic perspectives.
2022-02-22 | Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency.
Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.
2020-09-08 | Pharmacotherapy options in pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis (PAP) is a heterogeneous group of rare diseases characterized by the abnormal production and impaired degradation of pulmonary surfactant as a result of malfunctioning of alveolar macrophages. This is due to the downstream dysregulation of the GM-CSF pathway, which can be caused by specific autoantibodies (autoimmune, aPAP formerly known as idiopathic iPAP), direct injury to alveolar macrophages (e.g. by toxic inhaled agents.), or by genetic defects (hereditary or congenital PAP). Few pharmacotherapy options are currently available to treat this disease. The authors discuss the exogenous administration of GM-CSF, rituximab, and the potential role of cholesterol lowering medications in this review. The authors, furthermore, provide their opinion on the available pharmacotherapeutic options and give their future perspectives. Inhaled GM-CSF remains the most commonly used therapy in patients with iPAP but other inhaled therapies such as PPARγ activators should be considered, especially in patients who are partially responsive or unresponsive to traditional treatments.
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2023-06-14 | Alveolar macrophages in pulmonary alveolar proteinosis: origin, function, and therapeutic strategies
Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar macrophages (AMs) have been identified as playing a pivotal role in the pathogenesis of PAP. In most of PAP cases, the disease is triggered by impaired cholesterol clearance in AMs that depend on granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in defective alveolar surfactant clearance and disruption of pulmonary homeostasis. Currently, novel pathogenesis-based therapies are being developed that target the GM-CSF signaling, cholesterol homeostasis, and immune modulation of AMs. In this review, we summarize the origin and functional role of AMs in PAP, as well as the latest therapeutic strategies aimed at addressing this disease. Our goal is to provide new perspectives and insights into the pathogenesis of PAP, and thereby identify promising new treatments for this disease.
2017-09-16 | Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis
Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN-γ released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP. Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN-γ released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP.
2009-10-01 | Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages
Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of pulmonary surfactant, respiratory insufficiency, and increased infections. It occurs in various clinical settings that disrupt surfactant catabolism in alveolar macrophages, including a relatively more common autoimmune disease caused by GM-CSF autoantibodies and a rare congenital disease caused by CSF2RA mutations. Recent results demonstrate that GM-CSF is crucial for alveolar macrophage terminal differentiation and immune functions, pulmonary surfactant homeostasis, and lung host defense. GM-CSF is also required to determine the basal functional capacity of circulating neutrophils, including adhesion, phagocytosis, and microbial killing. PAP research has illuminated the crucial role of GM-CSF in innate immunity and led to novel therapy for PAP and the potential use of anti-GM-CSF therapy in other common disorders.
2006-01-12 | Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration
Abstract: 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.
1997-12-01 | GM-CSF Gene Expression Is Normal but Protein Release Is Absent in a Patient with Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by an excessive accumulation of surfactant lipids and proteins in the alveolar space. In mice with a homozygous deletion of granulocyte macrophage-colony stimulating factor (GM-CSF), their phenotype mimics PAP. To evaluate whether the knockout mouse model mimics human disease, we evaluated GM-CSF expression in alveolar macrophages from a patient with PAP. We performed multiple whole lung lavages on a patient with PAP, and cultured BAL cells in the presence or absence of LPS. In contrast to the GM-CSF knockout mouse, human BAL cells from a patient with PAP expressed mRNA for GM-CSF following LPS stimulation. However, similar to the knockout mouse, GM-CSF protein release from BAL cells was undetectable with or without LPS. BAL cells from normal human controls released GM-CSF in abundance after LPS stimulation. In BAL cells from the patient with PAP, neutralization of interleukin-10 (IL-10) by anti-IL-10 antibody, resulted in enhanced GM-CSF production. Thus, alveolar macrophages from a PAP lung have deficient GM-CSF production analogous to the GM-CSF knockout mice; in contrast, human cells from a PAP lung have an intact GM-CSF gene. This case report illustrates an important difference between the knockout mouse model of PAP and the human disease. Tchou-Wong K-M, Harkin TJ, Chi C, Bodkin M, Rom WN. GM-CSF gene expression is normal but protein release is absent in a patient with pulmonary alveolar proteinosis.
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