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Classifications

Harrison's Part

📘

Definitions

1

Serologic case definition of autoimmune PAP

A PAP syndrome (alveolar surfactant accumulation demonstrated by HRCT plus BAL cytology or lung biopsy) in which serum GM-CSF autoantibody testing is positive, distinguishing the autoimmune form from hereditary PAP (CSF2RA/CSF2RB defects) and secondary PAP.

OTHER

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Pathogenesis is driven by GM-CSF (granulocyte/macrophage colony-stimulating factor) autoantibodies, which are present at high concentrations in blood and tissues and form the basis of an accurate, commercially available diagnostic blood test with sensitivity and specificity of 100%."

The state-of-the-art review establishes the serum GM-CSF autoantibody test as the defining diagnostic criterion, with reported sensitivity and specificity of 100%.

👪

Inheritance

1

Not inherited (acquired autoimmune disease with HLA-linked susceptibility)

aPAP is an acquired autoimmune disease rather than a Mendelian disorder; no familial transmission was observed in the Japanese registry cohort, although a GWAS demonstrates an HLA class II heritable susceptibility component.

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."

No familial onset occurred among 223 registry patients, supporting an acquired rather than Mendelian mode.

?

Discussions and Knowledge Gaps

2

Does any available animal model reproduce the autoimmune arm of aPAP - the breakdown of tolerance to GM-CSF and sustained endogenous autoantibody production - rather than only the downstream GM-CSF-signaling loss modelled by Csf2 and Csf2rb knockouts?

HUMAN MODEL MISMATCH OPEN gap_apap_autoantibody_mediated_animal_model

Attached to

pathophysiology#Loss of Immune Tolerance to GM-CSF pathophysiology#GM-CSF Neutralization and Functional GM-CSF Deficiency

The standard model systems for PAP are germline knockouts of GM-CSF or its receptor, which faithfully reproduce the surfactant-clearance and foamy-macrophage phenotype but begin downstream of the autoimmune lesion: they model hereditary, not autoimmune, PAP. The one experiment that does reproduce the autoimmune arm - passive transfer of purified patient-derived GM-CSF autoantibody into macaques - is a passive-transfer challenge in a non-human primate, not a self-sustaining model of tolerance breakdown, and it does not recapitulate the HLA-DRB1*08:03-associated origin of the autoantibody response. Consequently, therapies aimed at the upstream autoimmune trigger (B-cell depletion, tolerance induction) cannot be evaluated preclinically in the way that surfactant-clearance therapies can, which is a concrete translational limitation rather than merely an unexplored question.

Proposed experiments

Active-immunization or humanized-HLA model of endogenous anti-GM-CSF autoimmunity

exp_apap_induced_autoimmunity_model

Develop a model in which endogenous anti-GM-CSF autoantibody production is induced and sustained rather than passively transferred, so that tolerance-directed therapies can be evaluated preclinically. Confirm that autoantibody rises above the reported critical threshold and that alveolar surfactant accumulation and foamy alveolar macrophages follow.

HLA-DRB1*08:03 transgenic GM-CSF immunization challenge

exp_apap_hla_drb1_0803_transgenic_challenge

Immunize HLA-DRB1*08:03 transgenic mice with GM-CSF and determine whether the risk allele permits breakdown of tolerance and development of alveolar surfactant accumulation, directly testing the MHC class II presentation hypothesis implied by the human GWAS.

Show evidence (1 reference)

PMID:20042763 SUPPORT Model Organism

"Together, these results show that GM-CSF autoantibodies reproduce the pathologic manifestations of idiopathic pulmonary alveolar proteinosis and provide strong evidence of causality in human idiopathic pulmonary alveolar proteinosis"

Passive transfer of patient autoantibody into primates reproduces the pathology, but this is an antibody-challenge experiment rather than a model of endogenous tolerance breakdown.

Is the HLA-DRB1*08:03 association with aPAP generalizable beyond the Japanese population, or is the MHC contribution to aPAP risk ancestry-specific?

KNOWLEDGE GAP OPEN gap_apap_hla_association_replication

Attached to

pathophysiology#Loss of Immune Tolerance to GM-CSF

The only genome-wide significant genetic signal reported for aPAP comes from a single-ancestry Japanese study of 198 cases and 395 controls. Because aPAP occurs in individuals of all races and geographic regions at a similar prevalence, an ancestry-restricted MHC risk allele would imply either population-specific genetic architecture or a modest effect that smaller non-Japanese cohorts are underpowered to detect. The distinction matters for whether MHC class II presentation of GM-CSF is a general mechanism of tolerance loss in this disease or one of several routes to the same autoantibody endpoint.

Proposed experiments

Multi-ancestry HLA fine-mapping in non-Japanese aPAP cohorts

exp_apap_multiancestry_hla_finemapping

Assemble non-Japanese aPAP cohorts of sufficient size to detect an odds ratio near 5 at HLA-DRB1*08:03 and perform HLA imputation and fine-mapping to test whether the MHC class II signal replicates outside Japan.

HLA-DRB1*08:03 carriage versus anti-GM-CSF autoantibody concentration

exp_apap_hla_autoantibody_titre_correlation

In non-Japanese patients, test whether HLA-DRB1*08:03 carriage predicts anti-GM-CSF autoantibody concentration, which would support the allele acting through the magnitude of the autoantibody response independently of ancestry.

Show evidence (2 references)

PMID:33589587 SUPPORT Human Clinical

"Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry."

The GWAS is restricted to a single ancestry and a modest sample size, which bounds the generalizability of the HLA claim.

PMID:35227171 SUPPORT Human Clinical

"It has a prevalence of 7-10 per million; occurs in individuals of all races, geographic regions, sex, and socioeconomic status; and accounts for 90% of all patients with PAP syndrome."

The disease occurs across all populations, making an ancestry-restricted risk allele a substantive open question.

⚙

Pathophysiology

8

Loss of Immune Tolerance to GM-CSF

Loss of B-cell tolerance to GM-CSF, influenced by MHC class II background (HLA-DRB1*08:03), drives production of high-titre polyclonal neutralizing IgG autoantibodies against GM-CSF. Low-level GM-CSF autoantibodies are present in all healthy people, so disease requires crossing a critical concentration threshold rather than simply acquiring the antibody.

plasma cell CL:0000786

HLA-DRB1 hgnc:4948

immunoglobulin production GO:0002377 ↑ INCREASED humoral immune response GO:0006959 ↕ DYSREGULATED

Downstream

GM-CSF Neutralization and Functional GM-CSF Deficiency

Autoimmune antibody positivity

Show evidence (3 references)

PMID:10499925 SUPPORT Human Clinical

"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 founding study identifies the neutralizing anti-GM-CSF IgG autoantibody as the autoimmune basis of the disease.

PMID:19282464 SUPPORT Human Clinical

"The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined."

Disease onset is threshold-dependent: autoantibodies exist physiologically and only cause PAP above a critical concentration.

PMID:33589587 SUPPORT Human Clinical

"HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease"

MHC class II background modulates the magnitude of the autoantibody response, linking tolerance loss to genetic susceptibility.

GM-CSF Neutralization and Functional GM-CSF Deficiency

Circulating and alveolar autoantibodies bind GM-CSF and neutralize its bioactivity, producing a functional ligand deficiency despite normal CSF2 expression and an intact GM-CSF receptor. This is the ligand-side mirror of the receptor-side lesion (biallelic CSF2RA/CSF2RB defects) that causes hereditary PAP.

alveolar macrophage CL:0000583

cytokine-mediated signaling pathway GO:0019221 ↓ DECREASED JAK-STAT signaling downstream of the GM-CSF receptor GO:0007259 ↓ DECREASED

alveolus of lung UBERON:0002299

Downstream

Arrested Alveolar Macrophage Terminal Differentiation

Systemic Myeloid Host Defence Impairment

Show evidence (3 references)

PMID:10499925 SUPPORT In Vitro

"It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro."

The autoantibody directly binds and neutralizes GM-CSF bioactivity, establishing functional ligand deficiency. The demonstration is an in vitro binding/neutralization assay, hence IN_VITRO rather than HUMAN_CLINICAL; the human-clinical arm of this node is carried by the other evidence items.

PMID:32897035 SUPPORT Human Clinical

"It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant."

The trial report states the disruption of GM-CSF signaling required by alveolar macrophages for surfactant clearance.

PMID:35227171 SUPPORT Human Clinical

"Research has established GM-CSF as a pulmonary regulatory molecule critical to surfactant homeostasis, alveolar stability, lung function, and host defense."

GM-CSF is the regulatory node whose neutralization explains both the surfactant and the host-defence arms of the disease.

Arrested Alveolar Macrophage Terminal Differentiation

Without GM-CSF signaling, alveolar macrophages fail to complete terminal differentiation, in particular failing to sustain the PU.1/PPAR-gamma transcriptional program that licenses surfactant lipid catabolism and cholesterol efflux.

alveolar macrophage CL:0000583

macrophage differentiation GO:0030225 ↓ DECREASED

alveolus of lung UBERON:0002299

Downstream

Impaired Surfactant Catabolism and Macrophage Cholesterol Overload

Show evidence (2 references)

PMID:10499925 SUPPORT Human Clinical

"our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance."

The causal chain from autoantibody to alveolar macrophage dysfunction to reduced surfactant clearance is stated directly.

PMID:35227171 SUPPORT Human Clinical

"Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency."

The review frames myeloid cell dysfunction as the defining cellular lesion of the disease.

Impaired Surfactant Catabolism and Macrophage Cholesterol Overload

Undifferentiated alveolar macrophages ingest surfactant but cannot catabolize its lipid or efflux the liberated cholesterol. Lipidomic analysis shows the accumulating species is predominantly cholesterol rather than phospholipid, reframing PAP as a disorder of macrophage cholesterol handling and identifying the foamy macrophage as a cholesterol-engorged cell.

alveolar macrophage CL:0000583

cholesterol efflux GO:0033344 ↓ DECREASED lipid catabolic process GO:0016042 ↓ DECREASED

alveolus of lung UBERON:0002299

Downstream

Alveolar Surfactant Accumulation

Show evidence (2 references)

PMID:30087322 SUPPORT Human Clinical

"In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids."

Direct lipidomic measurement in patients establishes cholesterol, not phospholipid, as the dominant accumulating species.

PMID:30087322 SUPPORT Model Organism

"In Csf2rb-/- mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages."

Reversing macrophage cholesterol overload in a GM-CSF-signaling-deficient mouse ameliorates disease, supporting cholesterol overload as causal rather than incidental.

Alveolar Surfactant Accumulation

PAS-positive lipoproteinaceous surfactant accumulates within foamy alveolar macrophages and free in the alveolar spaces, filling the airspaces while the alveolar walls remain well preserved. This produces the crazy-paving HRCT pattern and blocks gas exchange.

alveolar macrophage CL:0000583 pulmonary alveolar type 2 cell CL:0002063

surfactant homeostasis GO:0043129 ↕ DYSREGULATED

alveolus of lung UBERON:0002299

Downstream

Impaired Gas Exchange and Hypoxaemic Respiratory Insufficiency

Crazy paving pattern on pulmonary HRCT

Foam cells

Cough with scant frothy sputum

Crackles

Secondary Pulmonary Fibrosis

Show evidence (2 references)

PMID:30846703 SUPPORT Human Clinical

"Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages."

The disease primer defines the syndrome by alveolar surfactant accumulation with alveolar macrophage dysfunction.

PMID:20042763 SUPPORT Model Organism

"A diffuse, patchy distribution of lung lesions composed of well-preserved alveoli filled with eosinophilic, lipoproteinaceous material and enlarged, foamy alveolar macrophages developed in the macaques that received GM-CSF autoantibodies"

Passive transfer of patient-derived autoantibody into healthy primates reproduced the exact alveolar lesion, supporting causality.

Impaired Gas Exchange and Hypoxaemic Respiratory Insufficiency

Airspace filling widens the alveolar-arterial oxygen gradient and lowers the diffusing capacity, producing exertional dyspnoea, hypoxaemia and, when progressive, respiratory failure.

alveolus of lung UBERON:0002299

Downstream

Exertional dyspnoea

Hypoxemia

Cyanosis

Respiratory failure

Polycythemia

Restrictive ventilatory defect

Show evidence (1 reference)

PMID:30846703 SUPPORT Human Clinical

"PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."

The primer states the clinical consequences of airspace filling.

Systemic Myeloid Host Defence Impairment

GM-CSF also primes neutrophil and macrophage antimicrobial function, so autoantibody-mediated GM-CSF neutralization produces an acquired innate immunodeficiency in parallel with the surfactant lesion. This is an independent arm of the disease, and it explains the predisposition to opportunistic infection.

neutrophil CL:0000775 alveolar macrophage CL:0000583

phagocytosis GO:0006909 ↓ DECREASED

Downstream

Recurrent respiratory infections

Opportunistic infection

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency."

Innate immune deficiency is listed as a defining feature alongside the surfactant abnormality, not merely a complication.

PMID:19282464 SUPPORT Human Clinical

"GM-CSF autoantibodies were detected in all healthy subjects evaluated (n = 72) at low levels sufficient to rheostatically regulate multiple myeloid functions."

GM-CSF autoantibody levels rheostatically set myeloid function, so pathologic elevation suppresses myeloid host defence.

Secondary Pulmonary Fibrosis

A minority of patients develop pulmonary fibrosis over years of follow-up, a rare but potentially life-threatening complication of long-standing alveolar surfactant retention.

lung UBERON:0002048

Show evidence (2 references)

PMID:30846703 SUPPORT Human Clinical

"PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."

Pulmonary fibrosis is recognized as a late outcome of PAP.

PMID:35227171 SUPPORT Human Clinical

"The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."

The review lists fibrosis among the late complications in a subset.

✶

Histopathology

1

PAS-positive alveolar lipoproteinaceous material with foamy macrophages

Bronchoalveolar lavage yields grossly milky fluid; cytology and biopsy show granular eosinophilic PAS-positive proteinaceous material and enlarged foamy alveolar macrophages with well-preserved alveolar walls.

Show evidence (2 references)

PMID:20042763 SUPPORT Model Organism

"Ultrastructural evaluation revealed that alveolar macrophages were engorged with lipid droplets and lamellar inclusion bodies"

Ultrastructure of the autoantibody-induced primate lesion shows the lipid-engorged foamy macrophage that characterizes human aPAP.

PMID:20042763 SUPPORT Model Organism

"The bronchoalveolar-lavage fluid had a milky appearance and increased amounts of surfactant phospholipids and surfactant proteins as compared with the control fluid"

The characteristic milky, surfactant-rich lavage fluid was reproduced by autoantibody transfer.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Blood 1

Polycythemia HP:0001901

Severity: SEVERE

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"A thickened surfactant layer and surfactant-filled alveoli contribute to reduced oxygen delivery, resulting in hypoxemia, dyspnea, and in severe cases polycythemia, respiratory failure, and death."

Places polycythaemia on the hypoxaemia limb of the disease, occurring in severe cases alongside respiratory failure.

PMID:35227171 SUPPORT Model Organism

"Polycythemia develops over time in the absence of GM-CSF signaling"

The same phenotype emerges in GM-CSF-signaling-deficient mice, corroborating it as a consequence of the shared mechanism.

Immune 1

Recurrent respiratory infections HP:0002205

In the Japanese registry, intercurrent illnesses including infections were infrequent, so the infection risk should not be over-weighted for typical aPAP; it is most relevant to opportunistic pathogens.

Show evidence (1 reference)

PMID:30846703 SUPPORT Human Clinical

"PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."

Secondary infection is an established consequence of the disease.

Integument 1

Cyanosis HP:0000961

Severity: SEVERE

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Generally, the physical examination is unremarkable but can identify crackles or even cyanosis in severe cases."

Cyanosis is reported on examination in severe cases.

Respiratory 4

Cough with scant frothy sputum HP:0012735

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"The most common presentation is dyspnea of insidious onset with or without cough, production of scant white and frothy sputum, and diffuse radiographic infiltrates in a previously healthy adult, but it can also occur in children as young as 3 years."

The review describes cough with scant frothy sputum as part of the presentation.

Hypoxemia HP:0012418

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."

Progressive hypoxaemic respiratory insufficiency is the core clinical course.

Restrictive ventilatory defect HP:0002091

Show evidence (3 references)

PMID:35227171 SUPPORT Human Clinical

"Lung volumes can be normal in patients with mild disease or may show a restrictive ventilatory pattern of impairment with lung volumes reduced in proportion to disease severity, especially in more advanced disease"

States the restrictive pattern directly, and bounds it to more advanced disease rather than to all patients.

PMID:35227171 SUPPORT Human Clinical

"Results of spirometry are normal in many patients with autoimmune PAP, limiting its diagnostic and prognostic utility."

Explicit counterweight: spirometry is frequently normal, so restriction must not be curated as a typical finding.

PMID:18202348 SUPPORT Human Clinical

"A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease."

The registry cohort corroborates that diffusing capacity, not spirometry, tracks disease severity.

Respiratory failure HP:0002878

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."

Respiratory failure and death occur in a subset of patients.

Constitutional 1

Chest pain HP:0100749

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Some patients also present with throat clearing, chest pain, chest congestion, or production of scant whitish sputum"

Chest pain is listed among the less common presenting symptoms.

Other 7

Exertional dyspnoea FREQUENT Exertional dyspnea HP:0002875

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"Dyspnea was the most common presenting symptom, occurring in 54.3%."

Quantifies dyspnoea in 54.3% of registry patients, supporting the FREQUENT (30-79%) band.

Crazy paving pattern on pulmonary HRCT HP:0025391

Characteristic but not diagnostic. The same pattern occurs in other PAP-causing diseases, cardiogenic pulmonary oedema, hypersensitivity pneumonitis, Pneumocystis pneumonia, lymphangitic carcinomatosis and acute lung injury, so it cannot separate aPAP from hereditary or secondary PAP.

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"reveals a pattern of ground-glass opacification resulting in polygonal shapes with sharp-angled borders and superimposed interlobular septal thickening"

The review describes the HRCT crazy-paving morphology directly: ground-glass opacification in sharply bordered polygonal shapes with superimposed interlobular septal thickening.

PMID:35227171 SUPPORT Human Clinical

"Although characteristic, this pattern is not diagnostic of autoimmune PAP and can also be seen in other PAP-causing diseases"

Carried as an explicit caveat: crazy paving is characteristic but not diagnostic, and does not distinguish aPAP from other PAP-causing diseases.

Foam cells HP:0003651

Show evidence (3 references)

PMID:20042763 SUPPORT Model Organism

"Ultrastructural evaluation revealed that alveolar macrophages were engorged with lipid droplets and lamellar inclusion bodies"

Documents the foamy, lipid-engorged alveolar macrophage.

PMID:35227171 SUPPORT Human Clinical

"Electron microscopic examination reveals the presence of surfactant sediment and foamy alveolar macrophages"

Human ultrastructural evidence, so the phenotype does not rest solely on the primate model.

PMID:35227171 SUPPORT Human Clinical

"Consequently, cytoplasmic cholesterol accumulates and is esterified and sequestered in intracytoplasmic lipid droplets (as a cellular protective mechanism) resulting in the characteristic foamy appearance and enhanced oil red O staining"

Explains the foamy appearance mechanistically as esterified cholesterol sequestered in lipid droplets, tying the phenotype to the cholesterol overload node rather than leaving it descriptive.

Crackles HP:0030830

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Generally, the physical examination is unremarkable but can identify crackles or even cyanosis in severe cases."

States that examination can identify crackles while noting it is usually unremarkable; frequency is deliberately omitted.

Opportunistic infection HP:0031690

Show evidence (3 references)

PMID:35227171 SUPPORT Human Clinical

"Autoimmune PAP is associated with an increased risk of serious infections, consistent with the observed impaired innate immune functions of myeloid cells, which include reduced phagocytosis, microbial killing, proinflammatory signaling, and others"

Ties the infection risk explicitly to impaired myeloid innate immune function rather than to airspace filling.

PMID:35227171 SUPPORT Human Clinical

"Causative organisms include community-acquired and opportunistic microbial pathogens"

Identifies opportunistic pathogens as causative organisms.

PMID:35227171 SUPPORT Human Clinical

"occur at presentation or during the clinical course, at intra- or extrapulmonary sites, consistent with the systemic innate immunodeficiency caused by disruption of GM-CSF signaling"

Establishes the extrapulmonary/systemic distribution that distinguishes this from ordinary pulmonary superinfection.

Autoimmune antibody positivity OBLIGATE HP:0030057

Show evidence (1 reference)

PMID:10499925 SUPPORT Human Clinical

"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."

The autoantibody was present in every autoimmune PAP patient examined and absent in comparators.

Digital clubbing (atypical) Clubbing of fingers HP:0100759

Show evidence (2 references)

PMID:35227171 REFUTE Human Clinical

"Digital clubbing is not a feature of autoimmune PAP."

The review states the negative unambiguously. Curated as REFUTE so the entry records the diagnostically useful negative rather than implying clubbing is a feature of aPAP.

PMID:35227171 REFUTE Human Clinical

"Digital clubbing, fever, and hemoptysis are not typical, and the latter two indicate that intercurrent infection may be present."

Groups clubbing with fever and haemoptysis as atypical findings that should redirect the diagnosis.

🧬

Genetic Associations

1

HLA-DRB1*08:03 susceptibility allele

Gene: HLA-DRB1 hgnc:4948 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (3 references)

PMID:33589587 SUPPORT Human Clinical

"HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal"

HLA fine-mapping of the genome-wide significant MHC signal identifies HLA-DRB1*08:03 as the driving risk allele.

PMID:33589587 SUPPORT Human Clinical

"HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease"

The risk allele is quantitatively linked to the pathogenic autoantibody, connecting genetic susceptibility to the effector mechanism.

PMID:33589587 SUPPORT Human Clinical

"Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production."

The authors frame the finding as a heritable predisposition to abnormal antibody production rather than Mendelian causation.

💊

Medical Actions

7

Whole Lung Lavage

Action: whole lung lavage Ontology label: Lavage NCIT:C38068

Sequential large-volume saline lavage of each lung under general anaesthesia physically removes accumulated alveolar surfactant. It remains the first-line therapy despite never having been tested in a randomized trial.

Mechanism Target:

INHIBITS Alveolar Surfactant Accumulation — Lavage mechanically clears the accumulated alveolar material, acting downstream of the uncorrected autoantibody and macrophage defect.

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Although whole-lung lavage remains the first-line therapy, inhaled GM-CSF is a promising pharmacotherapeutic approach demonstrated in well-controlled trials to be safe, well tolerated, and efficacious."

The review names whole-lung lavage as first-line therapy.

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Although whole-lung lavage remains the first-line therapy, inhaled GM-CSF is a promising pharmacotherapeutic approach demonstrated in well-controlled trials to be safe, well tolerated, and efficacious."

Establishes whole-lung lavage as standard first-line care.

Inhaled Molgramostim

Action: Pharmacotherapy NCIT:C15986

Agent: molgramostim NCIT:C77591

Once-daily inhaled recombinant human GM-CSF delivered directly to the alveolar compartment to overcome local autoantibody neutralization and restore alveolar macrophage GM-CSF signaling. Efficacy was shown in the phase 2/3 IMPALA trial (alveolar-arterial oxygen difference) and confirmed in the phase 3 IMPALA-2 trial (DLCO).

Mechanism Target:

ACTIVATES GM-CSF Neutralization and Functional GM-CSF Deficiency — Supplying exogenous GM-CSF into the alveolus restores receptor engagement despite the neutralizing autoantibody, correcting the functional ligand deficiency at its point of action.

Show evidence (1 reference)

PMID:32897035 SUPPORT Human Clinical

"It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant."

The trial rationale explicitly targets the disrupted GM-CSF signaling node that inhaled GM-CSF replaces.

Show evidence (3 references)

PMID:32897035 SUPPORT Human Clinical

"improvement was greater among patients receiving continuous molgramostim than among those receiving placebo"

The IMPALA randomized trial demonstrated superiority of continuous inhaled molgramostim over placebo on the alveolar-arterial oxygen difference.

PMID:40834301 SUPPORT Human Clinical

"Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP."

The phase 3 IMPALA-2 trial confirms benefit on gas transfer, the primary endpoint.

PMID:40834301 SUPPORT Human Clinical

"The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points"

Quantifies the DLCO gain on molgramostim at the primary endpoint (versus 3.8 percentage points on placebo).

Inhaled Sargramostim

Action: Pharmacotherapy NCIT:C15986

Agent: sargramostim NCIT:C1492

Inhaled recombinant human GM-CSF (sargramostim), evaluated in a Japanese multicentre phase II trial with a 62% response rate and a sustained effect, without change in serum autoantibody levels.

Mechanism Target:

ACTIVATES Arrested Alveolar Macrophage Terminal Differentiation — Local GM-CSF supplementation drives alveolar macrophage differentiation and restores surfactant clearance capacity without lowering autoantibody titre.

Show evidence (1 reference)

PMID:20167854 SUPPORT Human Clinical

"No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged."

Benefit occurs without reducing autoantibody, indicating the drug acts by restoring downstream signaling rather than removing the autoantibody.

Show evidence (2 references)

PMID:20167854 SUPPORT Human Clinical

"Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62%"

Quantifies the response rate to inhaled sargramostim.

PMID:20167854 SUPPORT Human Clinical

"Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP."

The trial conclusion supports safety, efficacy and durability.

Rituximab

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Anti-CD20 B-cell depletion (two 1,000 mg intravenous infusions 15 days apart) used for disease refractory to lavage and inhaled GM-CSF. In an open-label phase II trial oxygenation improved in seven of nine completers, and anti-GM-CSF IgG fell in lavage fluid though not in serum.

Mechanism Target:

INHIBITS Loss of Immune Tolerance to GM-CSF — Depleting CD20-positive B lymphocytes reduces autoantibody production, acting on the upstream autoimmune trigger rather than the downstream surfactant load. Because most antibody-secreting plasma cells lack CD20, the serum autoantibody pool is only partly affected.

Show evidence (1 reference)

PMID:21478218 SUPPORT Human Clinical

"Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids"

Autoantibody fell in the target organ but not in serum, supporting a partial effect on the autoantibody-producing compartment.

Show evidence (2 references)

PMID:21478218 SUPPORT Human Clinical

"Both arterial oxygen tension and alveolar-arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study."

The open-label trial's primary oxygenation endpoint improved in most completers.

PMID:21478218 SUPPORT Human Clinical

"reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ."

Links clinical response to lung-compartment autoantibody reduction, supporting the target-organ autoantibody model.

Plasmapheresis

Action: plasmapheresis Ontology label: Plasmapheresis NCIT:C15304

Therapeutic plasma exchange to lower circulating GM-CSF autoantibody in refractory disease. Evidence is limited to case-level reports with inconsistent responses, and some patients remain refractory despite documented antibody reduction.

Mechanism Target:

INHIBITS GM-CSF Neutralization and Functional GM-CSF Deficiency — Plasma exchange removes circulating GM-CSF autoantibody, aiming to relieve the neutralization of GM-CSF. The autoantibody pool is large enough that the removal rate cannot keep pace with it.

Show evidence (1 reference)

PMID:35227171 SUPPORT Other

"However, the procedure must be repeated frequently (daily for 2 wk) to reduce the very high autoantibody concentrations present"

The mechanism is sound but the required exchange frequency reflects the autoantibody burden, which is what limits the approach. Tagged OTHER because the source sentence attributes this to unpublished results (B. Trapnell) rather than to published clinical data.

Show evidence (1 reference)

PMID:35227171 REFUTE Other

"Thus, this approach appears impractical and unviable in our opinion."

The state-of-the-art review judges plasmapheresis impractical and unviable. Curated as REFUTE so the entry records the negative recommendation rather than implying plasmapheresis is a usable option. Tagged OTHER, not HUMAN_CLINICAL: the sentence is explicitly the authors' opinion ("in our opinion") resting on unpublished results, so this is expert judgement rather than published clinical data refuting the therapy.

Lung Transplantation

Action: lung transplantation Ontology label: Lung Transplantation NCIT:C15274

Reserved for severe disease refractory to all other therapy. PAP recurrence in the allograft has been reported, consistent with the persistence of the circulating autoantibody after transplantation.

Mechanism Target:

INHIBITS Secondary Pulmonary Fibrosis — Transplantation replaces the fibrotic lung once irreversible parenchymal distortion has made whole-lung lavage ineffective. It addresses the end-organ consequence, not the mechanism.

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"In patients with autoimmune PAP who develop pulmonary fibrosis, WLL becomes ineffective and lung transplantation is required; however, the autoimmune PAP lung disease returns and must be treated"

Establishes both the indication (fibrosis making lavage ineffective) and the boundary (disease returns in the allograft).

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"the autoimmune PAP lung disease returns and must be treated"

Recurrence in the allograft is the decisive caveat: because the causal autoantibody is systemic and persists after transplantation, the new lung is exposed to the same lesion and requires ongoing treatment.

Oral Statin Therapy (investigational)

Action: Pharmacotherapy NCIT:C15986

Agent: HMG-CoA reductase inhibitor NCIT:C1655

Pathogenesis-based repurposing that targets alveolar macrophage cholesterol overload rather than the autoantibody. Supported by patient-level observational improvement, ex vivo human macrophage data, and rescue in Csf2rb-deficient mice; not established practice.

Mechanism Target:

INHIBITS Impaired Surfactant Catabolism and Macrophage Cholesterol Overload — Statins lower alveolar macrophage cholesterol burden and increase cholesterol efflux, relieving the specific lipid lesion identified in PAP macrophages.

Show evidence (1 reference)

PMID:30087322 SUPPORT In Vitro

"ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages"

Direct ex vivo demonstration that statin lowers cholesterol in patient alveolar macrophages.

Show evidence (2 references)

PMID:30087322 SUPPORT Human Clinical

"Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages."

Observational human improvement plus ex vivo mechanism; note the human data are associational rather than randomized.

PMID:30087322 SUPPORT Other

"These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP."

Authors' overall conclusion. Tagged OTHER because it summarises pooled human observational, murine and ex vivo results rather than reporting a single study type; the human and mouse arms are cited separately above.

🌍

Environmental Factors

2

Cigarette smoking

Smoking is common in aPAP cohorts and is often described as a risk or aggravating factor, but the large registry study concluded that the disease was not strongly linked to smoking once ascertained systematically.

Show evidence (2 references)

PMID:18202348 SUPPORT Human Clinical

"A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."

Smoking history is frequent (56%) in the registry cohort, supporting an association but not a causal role.

PMID:18202348 REFUTE Human Clinical

"Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses."

The same cohort explicitly refutes a strong causal link to smoking or occupational exposure, so this exposure is curated as an association only.

Mechanism Target:

MODULATES Loss of Immune Tolerance to GM-CSF — Recorded as modulating rather than predisposing, because the entry's own best evidence declines to support a risk claim. The registry that documents smoking in 56 percent of patients is the same one that concludes the disease was not strongly linked to smoking once ascertainment was systematic, and both sentences are carried here so the reader meets the refutation at the point of the claim. A prevalence among patients is not a risk, and this link is drawn to record the association without asserting one.

Show evidence (2 references)

PMID:18202348 SUPPORT Human Clinical

"A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."

Registry cohort recording a smoking history in 56 percent of patients alongside dust exposure in 23 percent. Prevalence within the cohort, with no comparison group.

PMID:18202348 REFUTE Human Clinical

"Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses."

The same cohort concluding that the disease was not strongly linked to smoking, occupational exposure or other illnesses. Carried deliberately: it is the strongest statement this entry has about the exposure and it points away from a causal reading.

Inhaled dust exposure

Occupational or environmental dust exposure is reported in roughly a quarter of registry patients. Inhalational exposures such as silica are more firmly linked to secondary PAP than to the autoimmune form.

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."

Dust exposure is documented in 23% of the cohort.

Mechanism Target:

MODULATES Loss of Immune Tolerance to GM-CSF — Graded identically to the smoking link and refuted by the same sentence, which names occupational exposure alongside smoking among the things the disease was not strongly linked to. Worth adding what this exposure's own description says and the evidence does not: inhalational exposures such as silica are more firmly tied to the secondary form of this disease than to the autoimmune form modelled here, so a dust-driven case may be a different entity rather than this one with an exposure.

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."

Records dust exposure in 23 percent of the registry cohort. Prevalence among patients, without a comparison group.

🔬

Biochemical Markers

5

Serum GM-CSF autoantibody (PRESENT)

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"Pathogenesis is driven by GM-CSF (granulocyte/macrophage colony-stimulating factor) autoantibodies, which are present at high concentrations in blood and tissues and form the basis of an accurate, commercially available diagnostic blood test with sensitivity and specificity of 100%."

The serum autoantibody is both the pathogenic driver and the diagnostic test.

PMID:10499925 SUPPORT Human Clinical

"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."

The original description documents the discriminating presence of the autoantibody in autoimmune but not secondary PAP or controls.

Disease severity score correlates with DLCO and serum biomarkers but not autoantibody level (PRESENT)

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease."

Establishes that autoantibody concentration is not a severity biomarker, an important curation caveat for monitoring.

Serum KL-6 (PRESENT)

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"KL-6 has been shown to better predict disease progression and therapeutic need than serum lactate dehydrogenase or PaO2"

KL-6 outperforms LDH and PaO2 for predicting progression and need for treatment, making it the prognostic marker of choice.

PMID:35227171 SUPPORT Human Clinical

"these serum biomarkers can be useful to monitor disease activity over time"

Scopes the serum biomarker panel to disease monitoring rather than diagnosis, since the same markers rise in other lung diseases.

Serum surfactant proteins and other activity biomarkers (PRESENT)

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"the degree of increase correlates with disease severity"

The serum biomarker panel scales with disease severity.

PMID:35227171 SUPPORT Human Clinical

"but they can also be increased in individuals with other lung diseases"

Records the specificity limitation that blocks diagnostic use.

Serum lactate dehydrogenase (PRESENT)

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Routine laboratory tests are typically normal in autoimmune PAP except for serum lactate dehydrogenase, which is nonspecific but is elevated in proportion to disease severity"

LDH is the exception to otherwise normal routine laboratory testing and scales with severity.

🔬

Diagnosis

4

Serum GM-CSF autoantibody test

The defining diagnostic test. A serum GM-CSF autoantibody assay reliably identifies autoimmune PAP and separates it from hereditary PAP, secondary PAP, other lung diseases and healthy individuals, with reported sensitivity and specificity of 100%. Because low-level autoantibodies are ubiquitous in people without PAP, the test depends on a concentration threshold rather than on mere detection.

serum GM-CSF autoantibody measurement NCIT:C181397

Show evidence (3 references)

PMID:35227171 SUPPORT Human Clinical

"In patients with suspected or confirmed PAP, a serum GM-CSF autoantibody test (Figure 4A) should be performed because it is highly sensitive and specific for a diagnosis of autoimmune PAP, which accounts for 90% of all cases of PAP"

Establishes the serum autoantibody assay as the test to perform in suspected PAP.

PMID:35227171 SUPPORT Human Clinical

"a serum GM-CSF autoantibody test can reliably identify autoimmune PAP and can accurately distinguish it from other PAP-causing diseases, other lung diseases, and people without lung disease"

Documents the discriminating power of the assay against the full differential.

PMID:19282464 SUPPORT Human Clinical

"The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined."

The assay is threshold-based because low-level autoantibodies occur in all healthy people.

Bronchoalveolar lavage

BAL is usually diagnostic without biopsy. Bronchoscopy of the airways is unremarkable, but the lavage fluid is opaque and milky-white (tan or brown in smokers), forms a waxy sediment on standing, and shows PAS-positive extracellular material with enlarged foamy alveolar macrophages.

bronchoscopy with bronchoalveolar lavage NCIT:C38042

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"Bronchoscopic examination of the airways is unremarkable in autoimmune PAP, while BAL fluid has a distinctive, opaque, milky-white/yellow appearance in nonsmokers and a tan/brown appearance in smokers"

Describes the characteristic macroscopic lavage appearance.

PMID:35227171 SUPPORT Human Clinical

"BAL fluid usually appears opalescent and milky white (or brown in smokers) and contains a waxy sediment, which appears quickly on standing at room temperature or in the cold."

Records the waxy sediment that forms on standing.

High-resolution chest CT

HRCT shows ground-glass opacification in sharply bordered polygonal shapes with superimposed interlobular septal thickening (crazy paving). It establishes the PAP syndrome and correlates with severity, but does not identify which PAP aetiology is present.

high-resolution chest CT NCIT:C20644

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"reveals a pattern of ground-glass opacification resulting in polygonal shapes with sharp-angled borders and superimposed interlobular septal thickening"

Describes the HRCT appearance used to establish the PAP syndrome.

PMID:35227171 SUPPORT Human Clinical

"Although characteristic, this pattern is not diagnostic of autoimmune PAP and can also be seen in other PAP-causing diseases"

Bounds the imaging claim: HRCT supports the syndrome but cannot assign the aetiology, which is why the serum autoantibody test is required.

Recognition of diagnostic difficulty and delay

Low prevalence, nonspecific symptoms and imaging, minimal examination findings and normal routine laboratory results combine to cause frequent misdiagnosis as pneumonia and substantial diagnostic delay.

diagnostic difficulty and delay

Deliberately carries no NCIT binding: this entry records a property of the diagnostic process rather than a procedure, so no clinical-action term under NCIT:C25218 is an accurate fit.

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"The diagnosis of autoimmune PAP is challenged by its low prevalence, nonspecific symptoms and radiographic findings, minimal physical examination findings, and normal routine laboratory test results."

Enumerates the factors that make the diagnosis difficult.

PMID:35227171 SUPPORT Human Clinical

"Low prevalence and nonspecific clinical, radiological, and laboratory findings commonly lead to misdiagnosis as pneumonia and substantially delay an accurate diagnosis."

Records misdiagnosis as pneumonia and the resulting delay.

🩻

Imaging Findings

3

Crazy paving on chest CT

Interlobular septal thickening superimposed on ground-glass opacification. It establishes the PAP syndrome and correlates with severity, but is not diagnostic of the autoimmune form - the same pattern occurs in the other PAP-causing diseases and in cardiogenic oedema, hypersensitivity pneumonitis, Pneumocystis pneumonia and acute lung injury. Extent varies from involvement of some lobules to a homogeneous pattern throughout.

Ct

Crazy paving pattern HP:0025391 lung UBERON:0002048 Crazy paving pattern HP:0025391

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"(E) Image revealing a homogeneous pattern of crazy paving throughout all regions of the lung parenchyma."

Documents the crazy-paving appearance on chest CT in its diffuse, homogeneous form.

PMID:35227171 SUPPORT Human Clinical

"Although characteristic, this pattern is not diagnostic of autoimmune PAP and can also be seen in other PAP-causing diseases"

Bounds the finding: characteristic of the syndrome but unable to assign the aetiology, hence `diagnostic: false`.

Geographic ground-glass opacification with sharply demarcated lobular borders

Ground-glass opacification involving some but not all secondary lobules, producing sharply angled polygonal borders against normal lung - the "geographic" pattern. The abrupt demarcation between adjacent involved and spared lobules is the radiographic signature of alveolar filling with preserved alveolar architecture, and distinguishes it from the diffuse haze of interstitial disease.

Ct

Ground-glass opacification HP:0025179 lung UBERON:0002048

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"(C) Image showing ground-glass opacification involving some but not all secondary lobules"

Records the lobule-selective distribution that produces the geographic appearance. The quote stops at a clause boundary rather than running into the source's curly-quoted "geographic", which would introduce non-ASCII characters into the snippet.

Pulmonary fibrosis with traction bronchiectasis (late)

A minority of patients progress to established fibrosis with parenchymal distortion and traction bronchiectasis. This is the imaging correlate of the Secondary Pulmonary Fibrosis mechanism node and marks the point at which whole-lung lavage becomes ineffective and transplantation is considered.

Ct

Pulmonary fibrosis HP:0002206 lung UBERON:0002048

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"(F) Image revealing extensive pulmonary fibrosis with parenchymal distortion from traction bronchiectasis."

Documents the late fibrotic imaging phenotype in a patient who proceeded to bilateral lung transplantation.

📈

Progression

5

Insidious adult-onset presentation

Age: Median 51 years at diagnosis; reported from age 3 years upward

Most patients present as previously healthy adults with dyspnoea of insidious onset; the Japanese registry records a median diagnosis age of 51 years and a 2.1:1 male predominance, and paediatric cases occur.

Show evidence (2 references)

PMID:18202348 SUPPORT Human Clinical

"The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years."

The registry cohort defines the age and sex distribution at diagnosis.

PMID:35227171 SUPPORT Human Clinical

"The most common presentation is dyspnea of insidious onset with or without cough, production of scant white and frothy sputum, and diffuse radiographic infiltrates in a previously healthy adult, but it can also occur in children as young as 3 years."

The review characterizes the typical insidious adult presentation and the paediatric age floor.

Asymptomatic screen-detected disease

A substantial minority of patients are asymptomatic at diagnosis and are identified incidentally through health screening imaging.

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"Importantly, 31.8% of patients were asymptomatic and were identified by health screening."

Nearly a third of registry patients were asymptomatic at ascertainment.

Progressive hypoxaemic respiratory insufficiency and late complications

The course is variable, but progression to hypoxaemic respiratory insufficiency, secondary infection, pulmonary fibrosis, respiratory failure and death occurs in a subset.

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."

The review summarizes the disease trajectory and its late complications.

Spontaneous resolution

The course is not uniformly progressive. It resolves in a minority without treatment, which is why the three recognized trajectories are stable disease, progressive deterioration and spontaneous resolution, and why an uncontrolled improvement cannot be attributed to therapy.

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"The clinical course of autoimmune PAP comprises three patterns: stable disease, progressive deterioration, and spontaneous resolution"

Names the three trajectories, establishing that progression is only one of the recognized courses.

PMID:35227171 SUPPORT Human Clinical

"7.9% of cases were reported to have experienced spontaneous resolution"

Quantifies spontaneous resolution in the largest meta-analysis, bounding the size of the non-progressive subset.

Long-term survival and cause of death

Survival is measured in years rather than months, but mortality is front-loaded: most deaths occur within the first year after diagnosis. Respiratory failure is the leading cause of death, with uncontrolled infection second - the two arms of the mechanism (surfactant accumulation and myeloid host-defence impairment) are also the two leading killers.

Show evidence (2 references)

PMID:35227171 SUPPORT Human Clinical

"In the largest study reported to date, a meta-analysis of 343 patients with PAP revealed survival rates of 78% at 2 years, 75% at 5 years, and 68% at 10 years; more than 80% of deaths occurred within 12 months of diagnosis, and respiratory failure was the most common cause of death, followed by..."

Provides the survival curve, the front-loaded mortality timing and the ranked causes of death.

PMID:18202348 SUPPORT Human Clinical

"Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses."

Counterweight on ascertainment: the systematically ascertained registry cohort was milder than referral-based series, so pooled survival figures drawn largely from referral cohorts may understate survival.

📊

Prevalence

3

Worldwide

Point Prevalence 0.85 per 100,000 (0.7–1.0) 1–9 per 1,000,000

Review-level worldwide estimate of 7-10 cases per million, normalized to 0.7-1.0 per 100,000.

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"It has a prevalence of 7-10 per million; occurs in individuals of all races, geographic regions, sex, and socioeconomic status; and accounts for 90% of all patients with PAP syndrome."

The review reports worldwide prevalence of 7-10 per million and that autoimmune PAP accounts for 90% of the PAP syndrome.

Japan (national PAP registry cohort)

Point Prevalence 0.62 per 100,000 1–9 per 1,000,000

Japanese national registry minimum prevalence of 6.2 per million, from the same cohort that reports a minimum annual incidence of 0.49 per million.

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively."

The 223-patient Japanese registry cohort reports minimum prevalence of 6.2 per million and confirms that autoimmune PAP is 89.9% of PAP cases.

Japan (national PAP registry cohort)

Annual Incidence 0.049 per 100,000 <1 in 1,000,000

Minimum annual incidence of 0.49 per million in the Japanese registry.

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively."

Same registry cohort reports the minimum annual incidence.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autoimmune Pulmonary Alveolar Proteinosis:

Hereditary pulmonary alveolar proteinosis

Overlapping Features Biallelic CSF2RA or CSF2RB defects disable the same GM-CSF axis at the receptor. GM-CSF autoantibody testing is negative and onset is typically earlier.

Show evidence (1 reference)

PMID:30846703 SUPPORT Human Clinical

"hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits)"

The primer defines the hereditary form by CSF2RA/CSF2RB mutation.

Secondary pulmonary alveolar proteinosis

Overlapping Features PAP arising as a consequence of another disease (haematologic malignancy, immunodeficiency, chronic infection, or inhalational exposure) that reduces alveolar macrophage number or function; GM-CSF autoantibodies are absent.

Show evidence (1 reference)

PMID:18202348 SUPPORT Human Clinical

"Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP)."

The cohort paper defines the autoimmune versus secondary distinction.

Community-acquired pneumonia

Overlapping Features The nonspecific clinical and radiographic picture commonly leads to initial misdiagnosis as pneumonia, substantially delaying diagnosis.

Show evidence (1 reference)

PMID:35227171 SUPPORT Human Clinical

"Low prevalence and nonspecific clinical, radiological, and laboratory findings commonly lead to misdiagnosis as pneumonia and substantially delay an accurate diagnosis."

Misdiagnosis as pneumonia is explicitly identified as the common error.

📊

Related Datasets

1

Expression profiles and potential functions of long non-coding RNAs and mRNAs in autoimmune pulmonary alveolar proteinosis patients geo:GSE153957

Microarray profiling of peripheral blood from five aPAP patients and five healthy volunteers. The sample source is peripheral blood rather than lung tissue, so it interrogates the systemic/autoimmune arm of the disease rather than the alveolar lesion directly.

human MICROARRAY n=10

Findings

Large-scale differential expression of both lncRNAs and mRNAs distinguishes aPAP peripheral blood from healthy controls.

"In total, 12459 DE lncRNAs and 9331 DE mRNAs were identified in APAP patient samples."

Twelve differentially expressed lncRNAs survived qRT-PCR validation as candidate contributors to pathogenesis.

"A qRT-PCR validation of 20 DE lncRNAs and 20 mRNAs indicated that 12 DE lncRNAs may be involved in the pathogenesis of APAP."

PMID:33820876

Exploratory and small (n=5 per group). The reported lncRNA and ceRNA networks are hypothesis-generating and are deliberately NOT curated as pathophysiology nodes; no mechanistic claim in this entry rests on them.

Show evidence (1 reference)

PMID:33820876 SUPPORT Human Clinical

"we performed microarray analyses to identify differentially expressed (DE) lncRNAs and mRNAs between peripheral blood samples from five APAP patients and five healthy volunteers"

Defines the dataset design, sample source and cohort size.

🔬

Clinical Trials

2

NCT02702180 PHASE_III COMPLETED

IMPALA: randomised, double-blind, placebo-controlled multicentre trial of inhaled molgramostim in autoimmune PAP, comparing once-daily and intermittent (7 days on, 7 days off) dosing against placebo over 24 weeks, with change in the alveolar-arterial oxygen difference as the primary endpoint. The predecessor of IMPALA-2 (NCT04544293).

Target Phenotypes: Hypoxemia HP:0012418 Exertional dyspnea HP:0002875

Show evidence (2 references)

clinicaltrials:NCT02702180 SUPPORT Human Clinical

"A third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks."

The registry record documents the three-arm continuous/intermittent/placebo design.

PMID:32897035 SUPPORT Human Clinical

"improvement was greater among patients receiving continuous molgramostim than among those receiving placebo"

The published result: continuous daily dosing beat placebo, which is why IMPALA-2 carried the once-daily regimen forward.

NCT04544293 PHASE_III COMPLETED

IMPALA-2: phase 3, double-blind, placebo-controlled trial of once-daily inhaled molgramostim 300 micrograms for 48 weeks in 164 patients with autoimmune PAP, with change in hemoglobin-adjusted DLCO percent predicted at week 24 as the primary endpoint.

Target Phenotypes: Exertional dyspnea HP:0002875 Hypoxemia HP:0012418

Show evidence (1 reference)

PMID:40834301 SUPPORT Human Clinical

"A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo."

Documents the randomized population of the IMPALA-2 phase 3 trial.

🐁

Animal Models

2

Wild type, passively immunized with patient-derived GM-CSF autoantibody Cynomolgus macaque (Macaca fascicularis) Passive immunization / autoantibody transfer

Healthy primates given highly purified GM-CSF autoantibody from a patient, maintained at serum levels of 40 micrograms per millilitre or more for 10 months, developed the full alveolar lesion. This is the model that closed the causality argument and licensed renaming the disease from "idiopathic" to "autoimmune" PAP. Its limitation is definitional: it transfers the effector antibody rather than inducing tolerance breakdown, so it models the downstream half of the disease only. See the gap_apap_autoantibody_mediated_animal_model discussion.

Species

Cynomolgus macaque (Macaca fascicularis)

Genotype

Wild type, passively immunized with patient-derived GM-CSF autoantibody

Show evidence (2 references)

PMID:20042763 SUPPORT Model Organism

"We administered highly purified GM-CSF autoantibodies derived from a patient with idiopathic pulmonary alveolar proteinosis to healthy nonhuman primates (Macaca fascicularis)."

Defines the species and the passive-transfer design.

PMID:20042763 SUPPORT Model Organism

"A diffuse, patchy distribution of lung lesions composed of well-preserved alveoli filled with eosinophilic, lipoproteinaceous material and enlarged, foamy alveolar macrophages developed in the macaques that received GM-CSF autoantibodies"

The transferred autoantibody reproduced the human alveolar lesion, including the well-preserved alveolar walls.

Csf2, Csf2ra or Csf2rb knockout (Csf2KO, Csf2raKO, Csf2rbKO) Mouse (Mus musculus) Knockout

Germline disruption of GM-CSF or either GM-CSF receptor subunit produces spontaneous PAP that matches human autoimmune PAP physiologically, radiologically, histopathologically, biochemically and immunologically, and also reproduces the host-defence arm. Mechanistically, however, these mice model hereditary PAP: they ablate the axis at the ligand or receptor rather than by autoantibody, so they sit downstream of the autoimmune lesion. Because the lesion is genetic rather than autoimmune, the model cannot be used to evaluate tolerance-directed or B-cell-depleting therapy - the translational limitation recorded in the gap_apap_autoantibody_mediated_animal_model discussion.

Species

Mouse (Mus musculus)

Genotype

Csf2, Csf2ra or Csf2rb knockout (Csf2KO, Csf2raKO, Csf2rbKO)

Genes

CSF2 hgnc:2434 CSF2RA hgnc:2435 CSF2RB hgnc:2436

Show evidence (2 references)

PMID:35227171 SUPPORT Model Organism

"spontaneously develop PAP similar to autoimmune PAP regarding physiological, radiological, histopathological, biochemical, and immunological manifestations"

Establishes the breadth of phenocopy across GM-CSF and receptor-subunit knockouts.

PMID:30087322 SUPPORT Model Organism

"In Csf2rb-/- mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages."

The knockout is tractable for testing surfactant-clearance therapies, which is how the statin hypothesis was established preclinically.

{ }

Source YAML

click to show

name: Autoimmune Pulmonary Alveolar Proteinosis
category: Respiratory Disease
creation_date: "2026-08-01T23:40:00Z"
synonyms:
- Autoimmune PAP
- aPAP
- Idiopathic pulmonary alveolar proteinosis
- Acquired pulmonary alveolar proteinosis
- Primary autoimmune PAP
description: >
  Autoimmune pulmonary alveolar proteinosis (aPAP) is an acquired diffuse lung
  disease caused by high-titre neutralizing IgG autoantibodies against
  granulocyte-macrophage colony-stimulating factor (GM-CSF). Loss of GM-CSF
  bioactivity blocks terminal differentiation of alveolar macrophages, so the
  GM-CSF-PU.1-PPAR-gamma-dependent catabolism of surfactant lipid and the efflux
  of cholesterol fail; PAS-positive lipoproteinaceous surfactant then accumulates
  within foamy alveolar macrophages and free in the alveolar spaces while the
  alveolar walls remain well preserved. Patients present with insidious
  exertional dyspnoea, cough, hypoxaemia and a crazy-paving pattern on HRCT.
  Because GM-CSF also primes neutrophil and macrophage host defence, aPAP is
  simultaneously an autoimmune disease and an acquired innate immunodeficiency,
  predisposing to opportunistic infection. It accounts for roughly 90% of the
  pulmonary alveolar proteinosis syndrome and is mechanistically distinct from
  hereditary PAP (biallelic CSF2RA/CSF2RB defects, MONDO:0012580), which
  disables the same axis at the receptor rather than the ligand, and from
  secondary PAP, in which an underlying disease reduces alveolar macrophage
  number or function.
disease_term:
  preferred_term: autoimmune pulmonary alveolar proteinosis
  term:
    id: MONDO:0012579
    label: autoimmune pulmonary alveolar proteinosis
parents:
- Pulmonary alveolar proteinosis
- Autoimmune disease
classifications:
  harrisons_chapter:
  - classification_value: RESPIRATORY
    notes: >-
      Primary clinical home: the defining lesion is alveolar surfactant
      accumulation with hypoxaemia, and management is pulmonary (whole-lung
      lavage, inhaled GM-CSF).
    evidence:
    - reference: PMID:35227171
      reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by progressive accumulation of surfactant in pulmonary alveoli and resulting hypoxemia"
      explanation: >
        The review frames the disease by alveolar surfactant accumulation and
        hypoxaemia, placing it in the respiratory Part.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Secondary Part: the causal lesion is a neutralizing IgG autoantibody, and
      the disease is simultaneously an autoimmune disease and an acquired innate
      immunodeficiency. B-cell-depleting therapy targets this axis.
    evidence:
    - reference: PMID:10499925
      reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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)."
      explanation: >
        The founding study establishes the disease as autoimmune, supporting the
        second Part assignment alongside the respiratory one.
references:
- reference: PMID:35227171
  title: "Autoimmune Pulmonary Alveolar Proteinosis."
- reference: PMID:30846703
  title: "Pulmonary alveolar proteinosis."
- reference: PMID:14695413
  title: "Pulmonary alveolar proteinosis."
definitions:
- name: Serologic case definition of autoimmune PAP
  definition_type: OTHER
  description: >
    A PAP syndrome (alveolar surfactant accumulation demonstrated by HRCT plus
    BAL cytology or lung biopsy) in which serum GM-CSF autoantibody testing is
    positive, distinguishing the autoimmune form from hereditary PAP
    (CSF2RA/CSF2RB defects) and secondary PAP.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenesis is driven by GM-CSF (granulocyte/macrophage colony-stimulating factor) autoantibodies, which are present at high concentrations in blood and tissues and form the basis of an accurate, commercially available diagnostic blood test with sensitivity and specificity of 100%."
    explanation: >
      The state-of-the-art review establishes the serum GM-CSF autoantibody test
      as the defining diagnostic criterion, with reported sensitivity and
      specificity of 100%.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.85
  rate_low: 0.7
  rate_high: 1.0
  notes: >
    Review-level worldwide estimate of 7-10 cases per million, normalized to
    0.7-1.0 per 100,000.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It has a prevalence of 7-10 per million; occurs in individuals of all races, geographic regions, sex, and socioeconomic status; and accounts for 90% of all patients with PAP syndrome."
    explanation: >
      The review reports worldwide prevalence of 7-10 per million and that
      autoimmune PAP accounts for 90% of the PAP syndrome.
- population: Japan (national PAP registry cohort)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.62
  notes: >
    Japanese national registry minimum prevalence of 6.2 per million, from the
    same cohort that reports a minimum annual incidence of 0.49 per million.
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively."
    explanation: >
      The 223-patient Japanese registry cohort reports minimum prevalence of 6.2
      per million and confirms that autoimmune PAP is 89.9% of PAP cases.
- population: Japan (national PAP registry cohort)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.049
  notes: Minimum annual incidence of 0.49 per million in the Japanese registry.
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively."
    explanation: Same registry cohort reports the minimum annual incidence.
progression:
- phase: Insidious adult-onset presentation
  age_range: Median 51 years at diagnosis; reported from age 3 years upward
  notes: >
    Most patients present as previously healthy adults with dyspnoea of insidious
    onset; the Japanese registry records a median diagnosis age of 51 years and a
    2.1:1 male predominance, and paediatric cases occur.
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years."
    explanation: The registry cohort defines the age and sex distribution at diagnosis.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common presentation is dyspnea of insidious onset with or without cough, production of scant white and frothy sputum, and diffuse radiographic infiltrates in a previously healthy adult, but it can also occur in children as young as 3 years."
    explanation: >
      The review characterizes the typical insidious adult presentation and the
      paediatric age floor.
- phase: Asymptomatic screen-detected disease
  notes: >
    A substantial minority of patients are asymptomatic at diagnosis and are
    identified incidentally through health screening imaging.
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, 31.8% of patients were asymptomatic and were identified by health screening."
    explanation: Nearly a third of registry patients were asymptomatic at ascertainment.
- phase: Progressive hypoxaemic respiratory insufficiency and late complications
  notes: >
    The course is variable, but progression to hypoxaemic respiratory
    insufficiency, secondary infection, pulmonary fibrosis, respiratory failure
    and death occurs in a subset.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."
    explanation: The review summarizes the disease trajectory and its late complications.
- phase: Spontaneous resolution
  notes: >-
    The course is not uniformly progressive. It resolves in a minority without
    treatment, which is why the three recognized trajectories are stable
    disease, progressive deterioration and spontaneous resolution, and why an
    uncontrolled improvement cannot be attributed to therapy.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course of autoimmune PAP comprises three patterns: stable disease, progressive deterioration, and spontaneous resolution"
    explanation: >
      Names the three trajectories, establishing that progression is only one of
      the recognized courses.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "7.9% of cases were reported to have experienced spontaneous resolution"
    explanation: >
      Quantifies spontaneous resolution in the largest meta-analysis, bounding
      the size of the non-progressive subset.
- phase: Long-term survival and cause of death
  notes: >-
    Survival is measured in years rather than months, but mortality is
    front-loaded: most deaths occur within the first year after diagnosis.
    Respiratory failure is the leading cause of death, with uncontrolled
    infection second - the two arms of the mechanism (surfactant accumulation
    and myeloid host-defence impairment) are also the two leading killers.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the largest study reported to date, a meta-analysis of 343 patients with PAP revealed survival rates of 78% at 2 years, 75% at 5 years, and 68% at 10 years; more than 80% of deaths occurred within 12 months of diagnosis, and respiratory failure was the most common cause of death, followed by uncontrolled infection"
    explanation: >
      Provides the survival curve, the front-loaded mortality timing and the
      ranked causes of death.
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses."
    explanation: >
      Counterweight on ascertainment: the systematically ascertained registry
      cohort was milder than referral-based series, so pooled survival figures
      drawn largely from referral cohorts may understate survival.
inheritance:
- name: Not inherited (acquired autoimmune disease with HLA-linked susceptibility)
  description: >
    aPAP is an acquired autoimmune disease rather than a Mendelian disorder; no
    familial transmission was observed in the Japanese registry cohort, although
    a GWAS demonstrates an HLA class II heritable susceptibility component.
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."
    explanation: >
      No familial onset occurred among 223 registry patients, supporting an
      acquired rather than Mendelian mode.
genetic:
- name: HLA-DRB1*08:03 susceptibility allele
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  features: >
    A Japanese GWAS with HLA fine-mapping identified HLA-DRB1*08:03 as the lead
    MHC class II risk allele for aPAP, and the same allele is associated with
    higher anti-GM-CSF antibody levels, linking MHC class II presentation to the
    loss of tolerance to GM-CSF.
  evidence:
  - reference: PMID:33589587
    reference_title: "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal"
    explanation: >
      HLA fine-mapping of the genome-wide significant MHC signal identifies
      HLA-DRB1*08:03 as the driving risk allele.
  - reference: PMID:33589587
    reference_title: "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease"
    explanation: >
      The risk allele is quantitatively linked to the pathogenic autoantibody,
      connecting genetic susceptibility to the effector mechanism.
  - reference: PMID:33589587
    reference_title: "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production."
    explanation: >
      The authors frame the finding as a heritable predisposition to abnormal
      antibody production rather than Mendelian causation.
  notes: >
    The GWAS is a single-ancestry (Japanese) study of 198 cases and 395 controls;
    the HLA association has not been consistently replicated in other
    populations. See the KNOWLEDGE_GAP discussion on replication.
environmental:
- name: Cigarette smoking
  exposure_term:
    preferred_term: exposure to cigarette smoking
    term:
      id: ECTO:0100003
      label: exposure to cigarette smoking
  influences_mechanisms:
  - target: Loss of Immune Tolerance to GM-CSF
    environmental_effect: MODULATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recorded as modulating rather than predisposing, because the entry's own
      best evidence declines to support a risk claim. The registry that
      documents smoking in 56 percent of patients is the same one that
      concludes the disease was not strongly linked to smoking once
      ascertainment was systematic, and both sentences are carried here so the
      reader meets the refutation at the point of the claim. A prevalence
      among patients is not a risk, and this link is drawn to record the
      association without asserting one.
    evidence:
    - reference: PMID:18202348
      reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."
      explanation: >-
        Registry cohort recording a smoking history in 56 percent of patients
        alongside dust exposure in 23 percent. Prevalence within the cohort,
        with no comparison group.
    - reference: PMID:18202348
      reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses."
      explanation: >-
        The same cohort concluding that the disease was not strongly linked to
        smoking, occupational exposure or other illnesses. Carried
        deliberately: it is the strongest statement this entry has about the
        exposure and it points away from a causal reading.
  description: >
    Smoking is common in aPAP cohorts and is often described as a risk or
    aggravating factor, but the large registry study concluded that the disease
    was not strongly linked to smoking once ascertained systematically.
  presence: PRESENT
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."
    explanation: >
      Smoking history is frequent (56%) in the registry cohort, supporting an
      association but not a causal role.
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses."
    explanation: >
      The same cohort explicitly refutes a strong causal link to smoking or
      occupational exposure, so this exposure is curated as an association only.
- name: Inhaled dust exposure
  exposure_term:
    preferred_term: exposure to inhaled dust
    term:
      id: ECTO:7000001
      label: exposure to dust
  influences_mechanisms:
  - target: Loss of Immune Tolerance to GM-CSF
    environmental_effect: MODULATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Graded identically to the smoking link and refuted by the same sentence,
      which names occupational exposure alongside smoking among the things the
      disease was not strongly linked to. Worth adding what this exposure's
      own description says and the evidence does not: inhalational exposures
      such as silica are more firmly tied to the secondary form of this
      disease than to the autoimmune form modelled here, so a dust-driven case
      may be a different entity rather than this one with an exposure.
    evidence:
    - reference: PMID:18202348
      reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."
      explanation: >-
        Records dust exposure in 23 percent of the registry cohort. Prevalence
        among patients, without a comparison group.
  description: >
    Occupational or environmental dust exposure is reported in roughly a quarter
    of registry patients. Inhalational exposures such as silica are more firmly
    linked to secondary PAP than to the autoimmune form.
  presence: PRESENT
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur."
    explanation: Dust exposure is documented in 23% of the cohort.
pathophysiology:
- name: Loss of Immune Tolerance to GM-CSF
  description: >
    Loss of B-cell tolerance to GM-CSF, influenced by MHC class II background
    (HLA-DRB1*08:03), drives production of high-titre polyclonal neutralizing IgG
    autoantibodies against GM-CSF. Low-level GM-CSF autoantibodies are present in
    all healthy people, so disease requires crossing a critical concentration
    threshold rather than simply acquiring the antibody.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  - preferred_term: humoral immune response
    term:
      id: GO:0006959
      label: humoral immune response
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:10499925
    reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: >
      The founding study identifies the neutralizing anti-GM-CSF IgG
      autoantibody as the autoimmune basis of the disease.
  - reference: PMID:19282464
    reference_title: "Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined."
    explanation: >
      Disease onset is threshold-dependent: autoantibodies exist physiologically
      and only cause PAP above a critical concentration.
  - reference: PMID:33589587
    reference_title: "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease"
    explanation: >
      MHC class II background modulates the magnitude of the autoantibody
      response, linking tolerance loss to genetic susceptibility.
  downstream:
  - target: GM-CSF Neutralization and Functional GM-CSF Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10499925
      reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro."
      explanation: >
        The autoantibody produced by the tolerance defect is the agent that
        neutralizes GM-CSF, closing this edge. The binding and neutralization
        were demonstrated in a cell-free/cell-based assay, so this is IN_VITRO
        evidence even though the antibody was purified from patients.
  - target: Autoimmune antibody positivity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10499925
      reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: >
        Loss of tolerance manifests directly as detectable systemic
        autoantibody, which is the definitional laboratory phenotype.
- name: GM-CSF Neutralization and Functional GM-CSF Deficiency
  description: >
    Circulating and alveolar autoantibodies bind GM-CSF and neutralize its
    bioactivity, producing a functional ligand deficiency despite normal CSF2
    expression and an intact GM-CSF receptor. This is the ligand-side mirror of
    the receptor-side lesion (biallelic CSF2RA/CSF2RB defects) that causes
    hereditary PAP.
  role: central_effector
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: JAK-STAT signaling downstream of the GM-CSF receptor
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  evidence:
  - reference: PMID:10499925
    reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "It specifically bound GM-CSF and neutralized bioactivity of the cytokine in vitro."
    explanation: >
      The autoantibody directly binds and neutralizes GM-CSF bioactivity,
      establishing functional ligand deficiency. The demonstration is an
      in vitro binding/neutralization assay, hence IN_VITRO rather than
      HUMAN_CLINICAL; the human-clinical arm of this node is carried by the
      other evidence items.
  - reference: PMID:32897035
    reference_title: "Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant."
    explanation: >
      The trial report states the disruption of GM-CSF signaling required by
      alveolar macrophages for surfactant clearance.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Research has established GM-CSF as a pulmonary regulatory molecule critical to surfactant homeostasis, alveolar stability, lung function, and host defense."
    explanation: >
      GM-CSF is the regulatory node whose neutralization explains both the
      surfactant and the host-defence arms of the disease.
  downstream:
  - target: Arrested Alveolar Macrophage Terminal Differentiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10499925
      reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance."
      explanation: >
        States the edge explicitly: GM-CSF neutralization causes alveolar
        macrophage dysfunction.
  - target: Systemic Myeloid Host Defence Impairment
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19282464
      reference_title: "Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "GM-CSF autoantibodies were detected in all healthy subjects evaluated (n = 72) at low levels sufficient to rheostatically regulate multiple myeloid functions."
      explanation: >
        GM-CSF availability sets myeloid function rheostatically, so
        neutralization impairs host defence on the same axis.
- name: Arrested Alveolar Macrophage Terminal Differentiation
  description: >
    Without GM-CSF signaling, alveolar macrophages fail to complete terminal
    differentiation, in particular failing to sustain the PU.1/PPAR-gamma
    transcriptional program that licenses surfactant lipid catabolism and
    cholesterol efflux.
  role: effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: macrophage differentiation
    term:
      id: GO:0030225
      label: macrophage differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:10499925
    reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our findings strongly suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance."
    explanation: >
      The causal chain from autoantibody to alveolar macrophage dysfunction to
      reduced surfactant clearance is stated directly.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency."
    explanation: >
      The review frames myeloid cell dysfunction as the defining cellular lesion
      of the disease.
  downstream:
  - target: Impaired Surfactant Catabolism and Macrophage Cholesterol Overload
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30087322
      reference_title: "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids."
      explanation: >
        The undifferentiated macrophage's measured lipid phenotype is
        cholesterol overload, which is the content of this edge.
- name: Impaired Surfactant Catabolism and Macrophage Cholesterol Overload
  description: >
    Undifferentiated alveolar macrophages ingest surfactant but cannot catabolize
    its lipid or efflux the liberated cholesterol. Lipidomic analysis shows the
    accumulating species is predominantly cholesterol rather than phospholipid,
    reframing PAP as a disorder of macrophage cholesterol handling and
    identifying the foamy macrophage as a cholesterol-engorged cell.
  role: effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: cholesterol efflux
    term:
      id: GO:0033344
      label: cholesterol efflux
    modifier: DECREASED
  - preferred_term: lipid catabolic process
    term:
      id: GO:0016042
      label: lipid catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:30087322
    reference_title: "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids."
    explanation: >
      Direct lipidomic measurement in patients establishes cholesterol, not
      phospholipid, as the dominant accumulating species.
  - reference: PMID:30087322
    reference_title: "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Csf2rb-/- mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages."
    explanation: >
      Reversing macrophage cholesterol overload in a GM-CSF-signaling-deficient
      mouse ameliorates disease, supporting cholesterol overload as causal
      rather than incidental.
  downstream:
  - target: Alveolar Surfactant Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32897035
      reference_title: "Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant."
      explanation: >
        Failure of the macrophage clearance function is what allows surfactant
        to accumulate in the airspaces.
- name: Alveolar Surfactant Accumulation
  description: >
    PAS-positive lipoproteinaceous surfactant accumulates within foamy alveolar
    macrophages and free in the alveolar spaces, filling the airspaces while the
    alveolar walls remain well preserved. This produces the crazy-paving HRCT
    pattern and blocks gas exchange.
  role: effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  - preferred_term: pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: surfactant homeostasis
    term:
      id: GO:0043129
      label: surfactant homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages."
    explanation: >
      The disease primer defines the syndrome by alveolar surfactant
      accumulation with alveolar macrophage dysfunction.
  - reference: PMID:20042763
    reference_title: "Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A diffuse, patchy distribution of lung lesions composed of well-preserved alveoli filled with eosinophilic, lipoproteinaceous material and enlarged, foamy alveolar macrophages developed in the macaques that received GM-CSF autoantibodies"
    explanation: >
      Passive transfer of patient-derived autoantibody into healthy primates
      reproduced the exact alveolar lesion, supporting causality.
  downstream:
  - target: Impaired Gas Exchange and Hypoxaemic Respiratory Insufficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35227171
      reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A thickened surfactant layer and surfactant-filled alveoli contribute to reduced oxygen delivery, resulting in hypoxemia, dyspnea, and in severe cases polycythemia, respiratory failure, and death."
      explanation: >
        Directly links the accumulated alveolar surfactant to reduced oxygen
        delivery and its clinical consequences.
  - target: Crazy paving pattern on pulmonary HRCT
    causal_link_type: DIRECT
  - target: Foam cells
    causal_link_type: DIRECT
  - target: Cough with scant frothy sputum
    causal_link_type: DIRECT
  - target: Crackles
    causal_link_type: DIRECT
  - target: Secondary Pulmonary Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Gas Exchange and Hypoxaemic Respiratory Insufficiency
  description: >
    Airspace filling widens the alveolar-arterial oxygen gradient and lowers the
    diffusing capacity, producing exertional dyspnoea, hypoxaemia and, when
    progressive, respiratory failure.
  role: effector
  biological_scale: ORGANISM
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  evidence:
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."
    explanation: The primer states the clinical consequences of airspace filling.
  downstream:
  - target: Exertional dyspnoea
    causal_link_type: DIRECT
  - target: Hypoxemia
    causal_link_type: DIRECT
  - target: Cyanosis
    causal_link_type: DIRECT
  - target: Respiratory failure
    causal_link_type: DIRECT
  - target: Polycythemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Restrictive ventilatory defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Systemic Myeloid Host Defence Impairment
  description: >
    GM-CSF also primes neutrophil and macrophage antimicrobial function, so
    autoantibody-mediated GM-CSF neutralization produces an acquired innate
    immunodeficiency in parallel with the surfactant lesion. This is an
    independent arm of the disease, and it explains the predisposition to
    opportunistic infection.
  role: effector
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  biological_processes:
  - preferred_term: phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency."
    explanation: >
      Innate immune deficiency is listed as a defining feature alongside the
      surfactant abnormality, not merely a complication.
  - reference: PMID:19282464
    reference_title: "Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GM-CSF autoantibodies were detected in all healthy subjects evaluated (n = 72) at low levels sufficient to rheostatically regulate multiple myeloid functions."
    explanation: >
      GM-CSF autoantibody levels rheostatically set myeloid function, so
      pathologic elevation suppresses myeloid host defence.
  downstream:
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
  - target: Opportunistic infection
    causal_link_type: DIRECT
- name: Secondary Pulmonary Fibrosis
  description: >
    A minority of patients develop pulmonary fibrosis over years of follow-up,
    a rare but potentially life-threatening complication of long-standing
    alveolar surfactant retention.
  role: modifier
  biological_scale: TISSUE
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."
    explanation: Pulmonary fibrosis is recognized as a late outcome of PAP.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."
    explanation: The review lists fibrosis among the late complications in a subset.
imaging_findings:
- name: Crazy paving on chest CT
  modality: CT
  imaging_finding_term:
    preferred_term: Crazy paving pattern
    term:
      id: HP:0025391
      label: Crazy paving pattern
  phenotype_term:
    preferred_term: Crazy paving pattern
    term:
      id: HP:0025391
      label: Crazy paving pattern
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  diagnostic: false
  description: >-
    Interlobular septal thickening superimposed on ground-glass opacification.
    It establishes the PAP syndrome and correlates with severity, but is not
    diagnostic of the autoimmune form - the same pattern occurs in the other
    PAP-causing diseases and in cardiogenic oedema, hypersensitivity
    pneumonitis, Pneumocystis pneumonia and acute lung injury. Extent varies
    from involvement of some lobules to a homogeneous pattern throughout.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(E) Image revealing a homogeneous pattern of crazy paving throughout all regions of the lung parenchyma."
    explanation: >
      Documents the crazy-paving appearance on chest CT in its diffuse,
      homogeneous form.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although characteristic, this pattern is not diagnostic of autoimmune PAP and can also be seen in other PAP-causing diseases"
    explanation: >
      Bounds the finding: characteristic of the syndrome but unable to assign
      the aetiology, hence `diagnostic: false`.
- name: Geographic ground-glass opacification with sharply demarcated lobular borders
  modality: CT
  imaging_finding_term:
    preferred_term: Ground-glass opacification
    term:
      id: HP:0025179
      label: Ground-glass opacification
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  diagnostic: false
  description: >-
    Ground-glass opacification involving some but not all secondary lobules,
    producing sharply angled polygonal borders against normal lung - the
    "geographic" pattern. The abrupt demarcation between adjacent involved and
    spared lobules is the radiographic signature of alveolar filling with
    preserved alveolar architecture, and distinguishes it from the diffuse
    haze of interstitial disease.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(C) Image showing ground-glass opacification involving some but not all secondary lobules"
    explanation: >
      Records the lobule-selective distribution that produces the geographic
      appearance. The quote stops at a clause boundary rather than running into
      the source's curly-quoted "geographic", which would introduce
      non-ASCII characters into the snippet.
- name: Pulmonary fibrosis with traction bronchiectasis (late)
  modality: CT
  imaging_finding_term:
    preferred_term: Pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  diagnostic: false
  description: >-
    A minority of patients progress to established fibrosis with parenchymal
    distortion and traction bronchiectasis. This is the imaging correlate of
    the Secondary Pulmonary Fibrosis mechanism node and marks the point at
    which whole-lung lavage becomes ineffective and transplantation is
    considered.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(F) Image revealing extensive pulmonary fibrosis with parenchymal distortion from traction bronchiectasis."
    explanation: >
      Documents the late fibrotic imaging phenotype in a patient who proceeded
      to bilateral lung transplantation.
histopathology:
- name: PAS-positive alveolar lipoproteinaceous material with foamy macrophages
  description: >
    Bronchoalveolar lavage yields grossly milky fluid; cytology and biopsy show
    granular eosinophilic PAS-positive proteinaceous material and enlarged foamy
    alveolar macrophages with well-preserved alveolar walls.
  diagnostic: true
  evidence:
  - reference: PMID:20042763
    reference_title: "Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ultrastructural evaluation revealed that alveolar macrophages were engorged with lipid droplets and lamellar inclusion bodies"
    explanation: >
      Ultrastructure of the autoantibody-induced primate lesion shows the
      lipid-engorged foamy macrophage that characterizes human aPAP.
  - reference: PMID:20042763
    reference_title: "Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The bronchoalveolar-lavage fluid had a milky appearance and increased amounts of surfactant phospholipids and surfactant proteins as compared with the control fluid"
    explanation: >
      The characteristic milky, surfactant-rich lavage fluid was reproduced by
      autoantibody transfer.
biochemical:
- name: Serum GM-CSF autoantibody
  presence: PRESENT
  specificity: >
    Diagnostic for the autoimmune form of PAP; reported sensitivity and
    specificity of 100% in the commercially available assay. Low-level GM-CSF
    autoantibodies are detectable in all healthy people, so the assay depends on
    a concentration threshold rather than mere detection.
  frequency: OBLIGATE
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenesis is driven by GM-CSF (granulocyte/macrophage colony-stimulating factor) autoantibodies, which are present at high concentrations in blood and tissues and form the basis of an accurate, commercially available diagnostic blood test with sensitivity and specificity of 100%."
    explanation: The serum autoantibody is both the pathogenic driver and the diagnostic test.
  - reference: PMID:10499925
    reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      The original description documents the discriminating presence of the
      autoantibody in autoimmune but not secondary PAP or controls.
  notes: >
    Autoantibody titre correlates poorly with disease severity; in the Japanese
    registry the severity score did not correlate with autoantibody level.
- name: Disease severity score correlates with DLCO and serum biomarkers but not autoantibody level
  presence: PRESENT
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease."
    explanation: >
      Establishes that autoantibody concentration is not a severity biomarker,
      an important curation caveat for monitoring.
- name: Serum KL-6
  presence: PRESENT
  specificity: >
    Not diagnostic - KL-6 is also elevated in other lung diseases - but it is the
    best-performing monitoring biomarker in aPAP, outperforming serum lactate
    dehydrogenase and PaO2 for predicting disease progression and therapeutic
    need. This is the counterpart to the curated negative that GM-CSF
    autoantibody titre does NOT track severity.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KL-6 has been shown to better predict disease progression and therapeutic need than serum lactate dehydrogenase or PaO2"
    explanation: >
      KL-6 outperforms LDH and PaO2 for predicting progression and need for
      treatment, making it the prognostic marker of choice.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these serum biomarkers can be useful to monitor disease activity over time"
    explanation: >
      Scopes the serum biomarker panel to disease monitoring rather than
      diagnosis, since the same markers rise in other lung diseases.
- name: Serum surfactant proteins and other activity biomarkers
  presence: PRESENT
  specificity: >
    Surfactant proteins (SP-A to SP-D), YKL-40, MCP-1 and CYFRA21-1 rise in
    proportion to disease severity but also rise in other lung diseases, which
    limits their diagnostic value while preserving their monitoring value.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the degree of increase correlates with disease severity"
    explanation: The serum biomarker panel scales with disease severity.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but they can also be increased in individuals with other lung diseases"
    explanation: Records the specificity limitation that blocks diagnostic use.
- name: Serum lactate dehydrogenase
  presence: PRESENT
  biomarker_term:
    preferred_term: Increased circulating lactate dehydrogenase concentration
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  specificity: >
    Nonspecific, but the one routine laboratory test that is characteristically
    abnormal; it rises in proportion to disease severity as measured by the
    alveolar-arterial oxygen difference.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Routine laboratory tests are typically normal in autoimmune PAP except for serum lactate dehydrogenase, which is nonspecific but is elevated in proportion to disease severity"
    explanation: >
      LDH is the exception to otherwise normal routine laboratory testing and
      scales with severity.
diagnosis:
- name: Serum GM-CSF autoantibody test
  description: >
    The defining diagnostic test. A serum GM-CSF autoantibody assay reliably
    identifies autoimmune PAP and separates it from hereditary PAP, secondary
    PAP, other lung diseases and healthy individuals, with reported sensitivity
    and specificity of 100%. Because low-level autoantibodies are ubiquitous in
    people without PAP, the test depends on a concentration threshold rather
    than on mere detection.
  diagnosis_term:
    preferred_term: serum GM-CSF autoantibody measurement
    term:
      id: NCIT:C181397
      label: Autoantibody Measurement
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with suspected or confirmed PAP, a serum GM-CSF autoantibody test (Figure 4A) should be performed because it is highly sensitive and specific for a diagnosis of autoimmune PAP, which accounts for 90% of all cases of PAP"
    explanation: Establishes the serum autoantibody assay as the test to perform in suspected PAP.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a serum GM-CSF autoantibody test can reliably identify autoimmune PAP and can accurately distinguish it from other PAP-causing diseases, other lung diseases, and people without lung disease"
    explanation: >
      Documents the discriminating power of the assay against the full
      differential.
  - reference: PMID:19282464
    reference_title: "Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined."
    explanation: >
      The assay is threshold-based because low-level autoantibodies occur in all
      healthy people.
- name: Bronchoalveolar lavage
  description: >
    BAL is usually diagnostic without biopsy. Bronchoscopy of the airways is
    unremarkable, but the lavage fluid is opaque and milky-white (tan or brown in
    smokers), forms a waxy sediment on standing, and shows PAS-positive
    extracellular material with enlarged foamy alveolar macrophages.
  diagnosis_term:
    preferred_term: bronchoscopy with bronchoalveolar lavage
    term:
      id: NCIT:C38042
      label: Bronchoscopy with Bronchoalveolar Lavage
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bronchoscopic examination of the airways is unremarkable in autoimmune PAP, while BAL fluid has a distinctive, opaque, milky-white/yellow appearance in nonsmokers and a tan/brown appearance in smokers"
    explanation: Describes the characteristic macroscopic lavage appearance.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BAL fluid usually appears opalescent and milky white (or brown in smokers) and contains a waxy sediment, which appears quickly on standing at room temperature or in the cold."
    explanation: Records the waxy sediment that forms on standing.
- name: High-resolution chest CT
  description: >
    HRCT shows ground-glass opacification in sharply bordered polygonal shapes
    with superimposed interlobular septal thickening (crazy paving). It
    establishes the PAP syndrome and correlates with severity, but does not
    identify which PAP aetiology is present.
  diagnosis_term:
    preferred_term: high-resolution chest CT
    term:
      id: NCIT:C20644
      label: High Resolution Computed Tomography
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reveals a pattern of ground-glass opacification resulting in polygonal shapes with sharp-angled borders and superimposed interlobular septal thickening"
    explanation: Describes the HRCT appearance used to establish the PAP syndrome.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although characteristic, this pattern is not diagnostic of autoimmune PAP and can also be seen in other PAP-causing diseases"
    explanation: >
      Bounds the imaging claim: HRCT supports the syndrome but cannot assign the
      aetiology, which is why the serum autoantibody test is required.
- name: Recognition of diagnostic difficulty and delay
  description: >
    Low prevalence, nonspecific symptoms and imaging, minimal examination
    findings and normal routine laboratory results combine to cause frequent
    misdiagnosis as pneumonia and substantial diagnostic delay.
  diagnosis_term:
    preferred_term: diagnostic difficulty and delay
  notes: >
    Deliberately carries no NCIT binding: this entry records a property of the
    diagnostic process rather than a procedure, so no clinical-action term under
    NCIT:C25218 is an accurate fit.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of autoimmune PAP is challenged by its low prevalence, nonspecific symptoms and radiographic findings, minimal physical examination findings, and normal routine laboratory test results."
    explanation: Enumerates the factors that make the diagnosis difficult.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low prevalence and nonspecific clinical, radiological, and laboratory findings commonly lead to misdiagnosis as pneumonia and substantially delay an accurate diagnosis."
    explanation: Records misdiagnosis as pneumonia and the resulting delay.
phenotypes:
- category: Respiratory
  name: Exertional dyspnoea
  frequency: FREQUENT
  description: >
    Progressive breathlessness of insidious onset is the commonest presenting
    symptom, recorded in 54.3% of the Japanese registry cohort at presentation.
  phenotype_term:
    preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dyspnea was the most common presenting symptom, occurring in 54.3%."
    explanation: >
      Quantifies dyspnoea in 54.3% of registry patients, supporting the FREQUENT
      (30-79%) band.
- category: Respiratory
  name: Cough with scant frothy sputum
  description: >
    Cough, often with scant white frothy sputum, accompanies dyspnoea in the
    typical presentation.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common presentation is dyspnea of insidious onset with or without cough, production of scant white and frothy sputum, and diffuse radiographic infiltrates in a previously healthy adult, but it can also occur in children as young as 3 years."
    explanation: The review describes cough with scant frothy sputum as part of the presentation.
- category: Respiratory
  name: Hypoxemia
  description: >
    Progressive hypoxaemia reflects the widening alveolar-arterial gradient from
    airspace filling and defines disease severity.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."
    explanation: Progressive hypoxaemic respiratory insufficiency is the core clinical course.
- category: Respiratory
  name: Crazy paving pattern on pulmonary HRCT
  description: >
    Ground-glass opacification with superimposed interlobular septal thickening,
    often sharply demarcated from normal lung, is the characteristic radiographic
    finding of alveolar filling.
  phenotype_term:
    preferred_term: Crazy paving pattern
    term:
      id: HP:0025391
      label: Crazy paving pattern
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reveals a pattern of ground-glass opacification resulting in polygonal shapes with sharp-angled borders and superimposed interlobular septal thickening"
    explanation: >
      The review describes the HRCT crazy-paving morphology directly: ground-glass
      opacification in sharply bordered polygonal shapes with superimposed
      interlobular septal thickening.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although characteristic, this pattern is not diagnostic of autoimmune PAP and can also be seen in other PAP-causing diseases"
    explanation: >
      Carried as an explicit caveat: crazy paving is characteristic but not
      diagnostic, and does not distinguish aPAP from other PAP-causing diseases.
  notes: >
    Characteristic but not diagnostic. The same pattern occurs in other
    PAP-causing diseases, cardiogenic pulmonary oedema, hypersensitivity
    pneumonitis, Pneumocystis pneumonia, lymphangitic carcinomatosis and acute
    lung injury, so it cannot separate aPAP from hereditary or secondary PAP.
- category: Respiratory
  name: Foam cells
  description: >
    Enlarged lipid-engorged foamy alveolar macrophages are recovered in lavage
    fluid and seen on biopsy.
  phenotype_term:
    preferred_term: Foam cells
    term:
      id: HP:0003651
      label: Foam cells
  evidence:
  - reference: PMID:20042763
    reference_title: "Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ultrastructural evaluation revealed that alveolar macrophages were engorged with lipid droplets and lamellar inclusion bodies"
    explanation: Documents the foamy, lipid-engorged alveolar macrophage.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopic examination reveals the presence of surfactant sediment and foamy alveolar macrophages"
    explanation: >
      Human ultrastructural evidence, so the phenotype does not rest solely on
      the primate model.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consequently, cytoplasmic cholesterol accumulates and is esterified and sequestered in intracytoplasmic lipid droplets (as a cellular protective mechanism) resulting in the characteristic foamy appearance and enhanced oil red O staining"
    explanation: >
      Explains the foamy appearance mechanistically as esterified cholesterol
      sequestered in lipid droplets, tying the phenotype to the cholesterol
      overload node rather than leaving it descriptive.
- category: Respiratory
  name: Restrictive ventilatory defect
  description: >
    Spirometry is normal in many patients. Restriction appears mainly in more
    advanced disease, with lung volumes falling in proportion to severity; the
    consistent physiologic abnormality is instead a reduced carbon monoxide
    diffusing capacity.
  phenotype_term:
    preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung volumes can be normal in patients with mild disease or may show a restrictive ventilatory pattern of impairment with lung volumes reduced in proportion to disease severity, especially in more advanced disease"
    explanation: >
      States the restrictive pattern directly, and bounds it to more advanced
      disease rather than to all patients.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Results of spirometry are normal in many patients with autoimmune PAP, limiting its diagnostic and prognostic utility."
    explanation: >
      Explicit counterweight: spirometry is frequently normal, so restriction
      must not be curated as a typical finding.
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease."
    explanation: >
      The registry cohort corroborates that diffusing capacity, not spirometry,
      tracks disease severity.
- category: Respiratory
  name: Crackles
  description: >
    Physical examination is generally unremarkable, but crackles may be heard.
  phenotype_term:
    preferred_term: Crackles
    term:
      id: HP:0030830
      label: Crackles
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generally, the physical examination is unremarkable but can identify crackles or even cyanosis in severe cases."
    explanation: >
      States that examination can identify crackles while noting it is usually
      unremarkable; frequency is deliberately omitted.
- category: Respiratory
  name: Cyanosis
  description: Cyanosis may be evident in severe disease.
  phenotype_term:
    preferred_term: Cyanosis
    term:
      id: HP:0000961
      label: Cyanosis
    severity: SEVERE
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generally, the physical examination is unremarkable but can identify crackles or even cyanosis in severe cases."
    explanation: Cyanosis is reported on examination in severe cases.
- category: Hematologic
  name: Polycythemia
  description: >
    Secondary polycythaemia develops in severe disease as an erythropoietic
    response to sustained hypoxaemia from surfactant-filled alveoli. It is a
    downstream consequence of impaired gas exchange rather than a primary
    haematologic lesion, and the same finding arises in mice lacking GM-CSF
    signaling.
  phenotype_term:
    preferred_term: Polycythemia
    term:
      id: HP:0001901
      label: Polycythemia
    severity: SEVERE
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A thickened surfactant layer and surfactant-filled alveoli contribute to reduced oxygen delivery, resulting in hypoxemia, dyspnea, and in severe cases polycythemia, respiratory failure, and death."
    explanation: >
      Places polycythaemia on the hypoxaemia limb of the disease, occurring in
      severe cases alongside respiratory failure.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Polycythemia develops over time in the absence of GM-CSF signaling"
    explanation: >
      The same phenotype emerges in GM-CSF-signaling-deficient mice,
      corroborating it as a consequence of the shared mechanism.
- category: Respiratory
  name: Chest pain
  description: >
    Some patients present with chest pain, throat clearing or chest congestion
    alongside the dominant dyspnoea and cough.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some patients also present with throat clearing, chest pain, chest congestion, or production of scant whitish sputum"
    explanation: Chest pain is listed among the less common presenting symptoms.
- category: Immunological
  name: Opportunistic infection
  description: >
    The GM-CSF-dependent myeloid defect produces an increased risk of serious
    infection with opportunistic organisms (Nocardia, mycobacteria, Aspergillus)
    at intrapulmonary and extrapulmonary sites, carrying a poor prognosis. This
    is the distinctive infectious consequence of the immunodeficiency arm, and
    it can occur without severe alveolar disease.
  phenotype_term:
    preferred_term: Opportunistic infection
    term:
      id: HP:0031690
      label: Opportunistic infection
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune PAP is associated with an increased risk of serious infections, consistent with the observed impaired innate immune functions of myeloid cells, which include reduced phagocytosis, microbial killing, proinflammatory signaling, and others"
    explanation: >
      Ties the infection risk explicitly to impaired myeloid innate immune
      function rather than to airspace filling.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Causative organisms include community-acquired and opportunistic microbial pathogens"
    explanation: Identifies opportunistic pathogens as causative organisms.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occur at presentation or during the clinical course, at intra- or extrapulmonary sites, consistent with the systemic innate immunodeficiency caused by disruption of GM-CSF signaling"
    explanation: >
      Establishes the extrapulmonary/systemic distribution that distinguishes
      this from ordinary pulmonary superinfection.
- category: Immunological
  name: Recurrent respiratory infections
  description: >
    The GM-CSF-dependent innate immune defect predisposes to secondary and
    opportunistic infection, including of the lung.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."
    explanation: Secondary infection is an established consequence of the disease.
  notes: >
    In the Japanese registry, intercurrent illnesses including infections were
    infrequent, so the infection risk should not be over-weighted for typical
    aPAP; it is most relevant to opportunistic pathogens.
- category: Immunological
  name: Autoimmune antibody positivity
  frequency: OBLIGATE
  description: >
    Serum and bronchoalveolar GM-CSF autoantibody positivity is definitional for
    the autoimmune form.
  phenotype_term:
    preferred_term: Autoimmune antibody positivity
    term:
      id: HP:0030057
      label: Autoimmune antibody positivity
  evidence:
  - reference: PMID:10499925
    reference_title: "Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      The autoantibody was present in every autoimmune PAP patient examined and
      absent in comparators.
- category: Respiratory
  name: Respiratory failure
  description: >
    Progressive airspace filling can culminate in respiratory failure and death
    in a subset of patients.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course, although variable, usually includes progressive hypoxemic respiratory insufficiency and, in some patients, secondary infections, pulmonary fibrosis, respiratory failure, and death."
    explanation: Respiratory failure and death occur in a subset of patients.
- category: Respiratory
  name: Digital clubbing (atypical)
  description: >
    Digital clubbing is explicitly NOT a feature of aPAP. Its presence, like
    fever or haemoptysis, should prompt consideration of an alternative or
    superimposed diagnosis such as intercurrent infection. Categorised under
    Respiratory rather than Skeletal because it functions here as a
    diagnostic negative for a lung disease.
  phenotype_term:
    preferred_term: Clubbing of fingers
    term:
      id: HP:0100759
      label: Clubbing of fingers
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Digital clubbing is not a feature of autoimmune PAP."
    explanation: >
      The review states the negative unambiguously. Curated as REFUTE so the
      entry records the diagnostically useful negative rather than implying
      clubbing is a feature of aPAP.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Digital clubbing, fever, and hemoptysis are not typical, and the latter two indicate that intercurrent infection may be present."
    explanation: >
      Groups clubbing with fever and haemoptysis as atypical findings that
      should redirect the diagnosis.
differential_diagnoses:
- name: Hereditary pulmonary alveolar proteinosis
  description: >
    Biallelic CSF2RA or CSF2RB defects disable the same GM-CSF axis at the
    receptor. GM-CSF autoantibody testing is negative and onset is typically
    earlier.
  evidence:
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits)"
    explanation: The primer defines the hereditary form by CSF2RA/CSF2RB mutation.
- name: Secondary pulmonary alveolar proteinosis
  description: >
    PAP arising as a consequence of another disease (haematologic malignancy,
    immunodeficiency, chronic infection, or inhalational exposure) that reduces
    alveolar macrophage number or function; GM-CSF autoantibodies are absent.
  evidence:
  - reference: PMID:18202348
    reference_title: "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP)."
    explanation: The cohort paper defines the autoimmune versus secondary distinction.
- name: Community-acquired pneumonia
  description: >
    The nonspecific clinical and radiographic picture commonly leads to initial
    misdiagnosis as pneumonia, substantially delaying diagnosis.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low prevalence and nonspecific clinical, radiological, and laboratory findings commonly lead to misdiagnosis as pneumonia and substantially delay an accurate diagnosis."
    explanation: Misdiagnosis as pneumonia is explicitly identified as the common error.
treatments:
- name: Whole Lung Lavage
  description: >
    Sequential large-volume saline lavage of each lung under general anaesthesia
    physically removes accumulated alveolar surfactant. It remains the first-line
    therapy despite never having been tested in a randomized trial.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: whole lung lavage
    term:
      id: NCIT:C38068
      label: Lavage
  target_mechanisms:
  - target: Alveolar Surfactant Accumulation
    treatment_effect: INHIBITS
    description: >
      Lavage mechanically clears the accumulated alveolar material, acting
      downstream of the uncorrected autoantibody and macrophage defect.
    evidence:
    - reference: PMID:35227171
      reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although whole-lung lavage remains the first-line therapy, inhaled GM-CSF is a promising pharmacotherapeutic approach demonstrated in well-controlled trials to be safe, well tolerated, and efficacious."
      explanation: The review names whole-lung lavage as first-line therapy.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although whole-lung lavage remains the first-line therapy, inhaled GM-CSF is a promising pharmacotherapeutic approach demonstrated in well-controlled trials to be safe, well tolerated, and efficacious."
    explanation: Establishes whole-lung lavage as standard first-line care.
  notes: >
    Symptomatic rather than mechanism-directed: it removes accumulated material
    without correcting the autoantibody or restoring macrophage differentiation,
    so relapse and repeat lavage are common.
- name: Inhaled Molgramostim
  description: >
    Once-daily inhaled recombinant human GM-CSF delivered directly to the alveolar
    compartment to overcome local autoantibody neutralization and restore alveolar
    macrophage GM-CSF signaling. Efficacy was shown in the phase 2/3 IMPALA trial
    (alveolar-arterial oxygen difference) and confirmed in the phase 3 IMPALA-2
    trial (DLCO).
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: molgramostim
      term:
        id: NCIT:C77591
        label: Molgramostim
  target_mechanisms:
  - target: GM-CSF Neutralization and Functional GM-CSF Deficiency
    treatment_effect: ACTIVATES
    description: >
      Supplying exogenous GM-CSF into the alveolus restores receptor engagement
      despite the neutralizing autoantibody, correcting the functional ligand
      deficiency at its point of action.
    evidence:
    - reference: PMID:32897035
      reference_title: "Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant."
      explanation: >
        The trial rationale explicitly targets the disrupted GM-CSF signaling
        node that inhaled GM-CSF replaces.
  evidence:
  - reference: PMID:32897035
    reference_title: "Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "improvement was greater among patients receiving continuous molgramostim than among those receiving placebo"
    explanation: >
      The IMPALA randomized trial demonstrated superiority of continuous inhaled
      molgramostim over placebo on the alveolar-arterial oxygen difference.
  - reference: PMID:40834301
    reference_title: "Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP."
    explanation: >
      The phase 3 IMPALA-2 trial confirms benefit on gas transfer, the primary
      endpoint.
  - reference: PMID:40834301
    reference_title: "Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points"
    explanation: >
      Quantifies the DLCO gain on molgramostim at the primary endpoint
      (versus 3.8 percentage points on placebo).
- name: Inhaled Sargramostim
  description: >
    Inhaled recombinant human GM-CSF (sargramostim), evaluated in a Japanese
    multicentre phase II trial with a 62% response rate and a sustained effect,
    without change in serum autoantibody levels.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sargramostim
      term:
        id: NCIT:C1492
        label: Sargramostim
  target_mechanisms:
  - target: Arrested Alveolar Macrophage Terminal Differentiation
    treatment_effect: ACTIVATES
    description: >
      Local GM-CSF supplementation drives alveolar macrophage differentiation and
      restores surfactant clearance capacity without lowering autoantibody titre.
    evidence:
    - reference: PMID:20167854
      reference_title: "Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged."
      explanation: >
        Benefit occurs without reducing autoantibody, indicating the drug acts
        by restoring downstream signaling rather than removing the autoantibody.
  evidence:
  - reference: PMID:20167854
    reference_title: "Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62%"
    explanation: Quantifies the response rate to inhaled sargramostim.
  - reference: PMID:20167854
    reference_title: "Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP."
    explanation: The trial conclusion supports safety, efficacy and durability.
- name: Rituximab
  description: >
    Anti-CD20 B-cell depletion (two 1,000 mg intravenous infusions 15 days apart)
    used for disease refractory to lavage and inhaled GM-CSF. In an open-label
    phase II trial oxygenation improved in seven of nine completers, and
    anti-GM-CSF IgG fell in lavage fluid though not in serum.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Loss of Immune Tolerance to GM-CSF
    treatment_effect: INHIBITS
    description: >
      Depleting CD20-positive B lymphocytes reduces autoantibody production,
      acting on the upstream autoimmune trigger rather than the downstream
      surfactant load. Because most antibody-secreting plasma cells lack CD20,
      the serum autoantibody pool is only partly affected.
    evidence:
    - reference: PMID:21478218
      reference_title: "An open-label trial of rituximab therapy in pulmonary alveolar proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids"
      explanation: >
        Autoantibody fell in the target organ but not in serum, supporting a
        partial effect on the autoantibody-producing compartment.
  evidence:
  - reference: PMID:21478218
    reference_title: "An open-label trial of rituximab therapy in pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both arterial oxygen tension and alveolar-arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study."
    explanation: The open-label trial's primary oxygenation endpoint improved in most completers.
  - reference: PMID:21478218
    reference_title: "An open-label trial of rituximab therapy in pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ."
    explanation: >
      Links clinical response to lung-compartment autoantibody reduction,
      supporting the target-organ autoantibody model.
  notes: >
    Evidence is a single-centre, open-label, 10-patient trial without a placebo
    group; durability and optimal dosing remain undefined.
- name: Plasmapheresis
  description: >
    Therapeutic plasma exchange to lower circulating GM-CSF autoantibody in
    refractory disease. Evidence is limited to case-level reports with
    inconsistent responses, and some patients remain refractory despite
    documented antibody reduction.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_mechanisms:
  - target: GM-CSF Neutralization and Functional GM-CSF Deficiency
    treatment_effect: INHIBITS
    description: >
      Plasma exchange removes circulating GM-CSF autoantibody, aiming to relieve
      the neutralization of GM-CSF. The autoantibody pool is large enough that
      the removal rate cannot keep pace with it.
    evidence:
    - reference: PMID:35227171
      reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "However, the procedure must be repeated frequently (daily for 2 wk) to reduce the very high autoantibody concentrations present"
      explanation: >
        The mechanism is sound but the required exchange frequency reflects the
        autoantibody burden, which is what limits the approach. Tagged OTHER
        because the source sentence attributes this to unpublished results
        (B. Trapnell) rather than to published clinical data.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "Thus, this approach appears impractical and unviable in our opinion."
    explanation: >
      The state-of-the-art review judges plasmapheresis impractical and
      unviable. Curated as REFUTE so the entry records the negative
      recommendation rather than implying plasmapheresis is a usable option.
      Tagged OTHER, not HUMAN_CLINICAL: the sentence is explicitly the authors'
      opinion ("in our opinion") resting on unpublished results, so this is
      expert judgement rather than published clinical data refuting the
      therapy.
  notes: >
    Retained for completeness of the therapeutic sequence and because the
    negative is informative: the mechanism is theoretically sound but defeated
    by the size of the autoantibody pool. Treat as not recommended rather than
    merely unproven.
- name: Lung Transplantation
  description: >
    Reserved for severe disease refractory to all other therapy. PAP recurrence
    in the allograft has been reported, consistent with the persistence of the
    circulating autoantibody after transplantation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: lung transplantation
    term:
      id: NCIT:C15274
      label: Lung Transplantation
  target_mechanisms:
  - target: Secondary Pulmonary Fibrosis
    treatment_effect: INHIBITS
    description: >
      Transplantation replaces the fibrotic lung once irreversible parenchymal
      distortion has made whole-lung lavage ineffective. It addresses the
      end-organ consequence, not the mechanism.
    evidence:
    - reference: PMID:35227171
      reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In patients with autoimmune PAP who develop pulmonary fibrosis, WLL becomes ineffective and lung transplantation is required; however, the autoimmune PAP lung disease returns and must be treated"
      explanation: >
        Establishes both the indication (fibrosis making lavage ineffective) and
        the boundary (disease returns in the allograft).
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the autoimmune PAP lung disease returns and must be treated"
    explanation: >
      Recurrence in the allograft is the decisive caveat: because the causal
      autoantibody is systemic and persists after transplantation, the new lung
      is exposed to the same lesion and requires ongoing treatment.
  notes: >
    Because the causal autoantibody is systemic and is not removed by replacing
    the lung, transplantation does not address the upstream mechanism, and PAP
    recurs in the allograft.
- name: Oral Statin Therapy (investigational)
  description: >
    Pathogenesis-based repurposing that targets alveolar macrophage cholesterol
    overload rather than the autoantibody. Supported by patient-level
    observational improvement, ex vivo human macrophage data, and rescue in
    Csf2rb-deficient mice; not established practice.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: HMG-CoA reductase inhibitor
      term:
        id: NCIT:C1655
        label: HMG-CoA Reductase Inhibitor
  target_mechanisms:
  - target: Impaired Surfactant Catabolism and Macrophage Cholesterol Overload
    treatment_effect: INHIBITS
    description: >
      Statins lower alveolar macrophage cholesterol burden and increase
      cholesterol efflux, relieving the specific lipid lesion identified in PAP
      macrophages.
    evidence:
    - reference: PMID:30087322
      reference_title: "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages"
      explanation: >
        Direct ex vivo demonstration that statin lowers cholesterol in patient
        alveolar macrophages.
  evidence:
  - reference: PMID:30087322
    reference_title: "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages."
    explanation: >
      Observational human improvement plus ex vivo mechanism; note the human
      data are associational rather than randomized.
  - reference: PMID:30087322
    reference_title: "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP."
    explanation: >
      Authors' overall conclusion. Tagged OTHER because it summarises pooled
      human observational, murine and ex vivo results rather than reporting a
      single study type; the human and mouse arms are cited separately above.
  notes: >
    Investigational. The supporting human evidence is observational, not a
    randomized controlled trial.
datasets:
- accession: geo:GSE153957
  title: >-
    Expression profiles and potential functions of long non-coding RNAs and
    mRNAs in autoimmune pulmonary alveolar proteinosis patients
  data_type: MICROARRAY
  sample_count: 10
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:33820876
  description: >-
    Microarray profiling of peripheral blood from five aPAP patients and five
    healthy volunteers. The sample source is peripheral blood rather than lung
    tissue, so it interrogates the systemic/autoimmune arm of the disease
    rather than the alveolar lesion directly.
  findings:
  - statement: >-
      Large-scale differential expression of both lncRNAs and mRNAs
      distinguishes aPAP peripheral blood from healthy controls.
    supporting_text: "In total, 12459 DE lncRNAs and 9331 DE mRNAs were identified in APAP patient samples."
  - statement: >-
      Twelve differentially expressed lncRNAs survived qRT-PCR validation as
      candidate contributors to pathogenesis.
    supporting_text: "A qRT-PCR validation of 20 DE lncRNAs and 20 mRNAs indicated that 12 DE lncRNAs may be involved in the pathogenesis of APAP."
  evidence:
  - reference: PMID:33820876
    reference_title: "Expression profiles and potential functions of long noncoding RNAs and mRNAs in autoimmune pulmonary alveolar proteinosis patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed microarray analyses to identify differentially expressed (DE) lncRNAs and mRNAs between peripheral blood samples from five APAP patients and five healthy volunteers"
    explanation: Defines the dataset design, sample source and cohort size.
  notes: >-
    Exploratory and small (n=5 per group). The reported lncRNA and ceRNA
    networks are hypothesis-generating and are deliberately NOT curated as
    pathophysiology nodes; no mechanistic claim in this entry rests on them.
animal_models:
- species: Cynomolgus macaque (Macaca fascicularis)
  genotype: Wild type, passively immunized with patient-derived GM-CSF autoantibody
  category: Passive immunization / autoantibody transfer
  associated_phenotypes:
  - Alveolar filling with lipoproteinaceous material
  - Foamy alveolar macrophages
  - Milky bronchoalveolar lavage fluid
  description: >-
    Healthy primates given highly purified GM-CSF autoantibody from a patient,
    maintained at serum levels of 40 micrograms per millilitre or more for 10
    months, developed the full alveolar lesion. This is the model that closed
    the causality argument and licensed renaming the disease from "idiopathic"
    to "autoimmune" PAP. Its limitation is definitional: it transfers the
    effector antibody rather than inducing tolerance breakdown, so it models
    the downstream half of the disease only. See the
    gap_apap_autoantibody_mediated_animal_model discussion.
  evidence:
  - reference: PMID:20042763
    reference_title: "Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We administered highly purified GM-CSF autoantibodies derived from a patient with idiopathic pulmonary alveolar proteinosis to healthy nonhuman primates (Macaca fascicularis)."
    explanation: Defines the species and the passive-transfer design.
  - reference: PMID:20042763
    reference_title: "Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A diffuse, patchy distribution of lung lesions composed of well-preserved alveoli filled with eosinophilic, lipoproteinaceous material and enlarged, foamy alveolar macrophages developed in the macaques that received GM-CSF autoantibodies"
    explanation: >
      The transferred autoantibody reproduced the human alveolar lesion,
      including the well-preserved alveolar walls.
- species: Mouse (Mus musculus)
  genotype: Csf2, Csf2ra or Csf2rb knockout (Csf2KO, Csf2raKO, Csf2rbKO)
  category: Knockout
  genes:
  - preferred_term: CSF2
    term:
      id: hgnc:2434
      label: CSF2
  - preferred_term: CSF2RA
    term:
      id: hgnc:2435
      label: CSF2RA
  - preferred_term: CSF2RB
    term:
      id: hgnc:2436
      label: CSF2RB
  associated_phenotypes:
  - Alveolar surfactant accumulation
  - Foamy alveolar macrophages
  - Susceptibility to microbial pathogens
  - Polycythemia
  description: >-
    Germline disruption of GM-CSF or either GM-CSF receptor subunit produces
    spontaneous PAP that matches human autoimmune PAP physiologically,
    radiologically, histopathologically, biochemically and immunologically, and
    also reproduces the host-defence arm. Mechanistically, however, these mice
    model hereditary PAP: they ablate the axis at the ligand or receptor rather
    than by autoantibody, so they sit downstream of the autoimmune lesion.
    Because the lesion is genetic rather than autoimmune, the model cannot be
    used to evaluate tolerance-directed or B-cell-depleting therapy - the
    translational limitation recorded in the
    gap_apap_autoantibody_mediated_animal_model discussion.
  evidence:
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "spontaneously develop PAP similar to autoimmune PAP regarding physiological, radiological, histopathological, biochemical, and immunological manifestations"
    explanation: >
      Establishes the breadth of phenocopy across GM-CSF and receptor-subunit
      knockouts.
  - reference: PMID:30087322
    reference_title: "Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Csf2rb-/- mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages."
    explanation: >
      The knockout is tractable for testing surfactant-clearance therapies,
      which is how the statin hypothesis was established preclinically.
clinical_trials:
- name: NCT02702180
  phase: PHASE_III
  status: COMPLETED
  description: >
    IMPALA: randomised, double-blind, placebo-controlled multicentre trial of
    inhaled molgramostim in autoimmune PAP, comparing once-daily and
    intermittent (7 days on, 7 days off) dosing against placebo over 24 weeks,
    with change in the alveolar-arterial oxygen difference as the primary
    endpoint. The predecessor of IMPALA-2 (NCT04544293).
  target_phenotypes:
  - preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  - preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
  evidence:
  - reference: clinicaltrials:NCT02702180
    reference_title: "A Randomised, Double-blind, Placebo-controlled Multicentre Clinical Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis Patients"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A third of the patients will receive inhaled molgramostim once daily for 24 weeks, a third will receive inhaled molgramostim intermittently (7 days on, 7 days off) for 24 weeks and a third will receive inhaled matching placebo for 24 weeks."
    explanation: The registry record documents the three-arm continuous/intermittent/placebo design.
  - reference: PMID:32897035
    reference_title: "Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "improvement was greater among patients receiving continuous molgramostim than among those receiving placebo"
    explanation: >
      The published result: continuous daily dosing beat placebo, which is why
      IMPALA-2 carried the once-daily regimen forward.
- name: NCT04544293
  phase: PHASE_III
  status: COMPLETED
  description: >
    IMPALA-2: phase 3, double-blind, placebo-controlled trial of once-daily
    inhaled molgramostim 300 micrograms for 48 weeks in 164 patients with
    autoimmune PAP, with change in hemoglobin-adjusted DLCO percent predicted at
    week 24 as the primary endpoint.
  target_phenotypes:
  - preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
  - preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:40834301
    reference_title: "Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo."
    explanation: Documents the randomized population of the IMPALA-2 phase 3 trial.
discussions:
- discussion_id: gap_apap_autoantibody_mediated_animal_model
  prompt: >-
    Does any available animal model reproduce the autoimmune arm of aPAP - the
    breakdown of tolerance to GM-CSF and sustained endogenous autoantibody
    production - rather than only the downstream GM-CSF-signaling loss modelled
    by Csf2 and Csf2rb knockouts?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Immune Tolerance to GM-CSF
  - pathophysiology#GM-CSF Neutralization and Functional GM-CSF Deficiency
  rationale: >-
    The standard model systems for PAP are germline knockouts of GM-CSF or its
    receptor, which faithfully reproduce the surfactant-clearance and
    foamy-macrophage phenotype but begin downstream of the autoimmune lesion:
    they model hereditary, not autoimmune, PAP. The one experiment that does
    reproduce the autoimmune arm - passive transfer of purified patient-derived
    GM-CSF autoantibody into macaques - is a passive-transfer challenge in a
    non-human primate, not a self-sustaining model of tolerance breakdown, and
    it does not recapitulate the HLA-DRB1*08:03-associated origin of the
    autoantibody response. Consequently, therapies aimed at the upstream
    autoimmune trigger (B-cell depletion, tolerance induction) cannot be
    evaluated preclinically in the way that surfactant-clearance therapies can,
    which is a concrete translational limitation rather than merely an
    unexplored question.
  proposed_experiments:
  - experiment_id: exp_apap_induced_autoimmunity_model
    name: Active-immunization or humanized-HLA model of endogenous anti-GM-CSF autoimmunity
    description: >-
      Develop a model in which endogenous anti-GM-CSF autoantibody production is
      induced and sustained rather than passively transferred, so that
      tolerance-directed therapies can be evaluated preclinically. Confirm that
      autoantibody rises above the reported critical threshold and that alveolar
      surfactant accumulation and foamy alveolar macrophages follow.
  - experiment_id: exp_apap_hla_drb1_0803_transgenic_challenge
    name: HLA-DRB1*08:03 transgenic GM-CSF immunization challenge
    description: >-
      Immunize HLA-DRB1*08:03 transgenic mice with GM-CSF and determine whether
      the risk allele permits breakdown of tolerance and development of alveolar
      surfactant accumulation, directly testing the MHC class II presentation
      hypothesis implied by the human GWAS.
  evidence:
  - reference: PMID:20042763
    reference_title: "Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, these results show that GM-CSF autoantibodies reproduce the pathologic manifestations of idiopathic pulmonary alveolar proteinosis and provide strong evidence of causality in human idiopathic pulmonary alveolar proteinosis"
    explanation: >
      Passive transfer of patient autoantibody into primates reproduces the
      pathology, but this is an antibody-challenge experiment rather than a
      model of endogenous tolerance breakdown.
- discussion_id: gap_apap_hla_association_replication
  prompt: >-
    Is the HLA-DRB1*08:03 association with aPAP generalizable beyond the
    Japanese population, or is the MHC contribution to aPAP risk
    ancestry-specific?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Immune Tolerance to GM-CSF
  rationale: >-
    The only genome-wide significant genetic signal reported for aPAP comes from
    a single-ancestry Japanese study of 198 cases and 395 controls. Because aPAP
    occurs in individuals of all races and geographic regions at a similar
    prevalence, an ancestry-restricted MHC risk allele would imply either
    population-specific genetic architecture or a modest effect that smaller
    non-Japanese cohorts are underpowered to detect. The distinction matters for
    whether MHC class II presentation of GM-CSF is a general mechanism of
    tolerance loss in this disease or one of several routes to the same
    autoantibody endpoint.
  proposed_experiments:
  - experiment_id: exp_apap_multiancestry_hla_finemapping
    name: Multi-ancestry HLA fine-mapping in non-Japanese aPAP cohorts
    description: >-
      Assemble non-Japanese aPAP cohorts of sufficient size to detect an odds
      ratio near 5 at HLA-DRB1*08:03 and perform HLA imputation and fine-mapping
      to test whether the MHC class II signal replicates outside Japan.
  - experiment_id: exp_apap_hla_autoantibody_titre_correlation
    name: HLA-DRB1*08:03 carriage versus anti-GM-CSF autoantibody concentration
    description: >-
      In non-Japanese patients, test whether HLA-DRB1*08:03 carriage predicts
      anti-GM-CSF autoantibody concentration, which would support the allele
      acting through the magnitude of the autoantibody response independently of
      ancestry.
  evidence:
  - reference: PMID:33589587
    reference_title: "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry."
    explanation: >
      The GWAS is restricted to a single ancestry and a modest sample size,
      which bounds the generalizability of the HLA claim.
  - reference: PMID:35227171
    reference_title: "Autoimmune Pulmonary Alveolar Proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It has a prevalence of 7-10 per million; occurs in individuals of all races, geographic regions, sex, and socioeconomic status; and accounts for 90% of all patients with PAP syndrome."
    explanation: >
      The disease occurs across all populations, making an ancestry-restricted
      risk allele a substantive open question.
notes: >
  Curated de novo from a claude_code deep-research report
  (research/Autoimmune_Pulmonary_Alveolar_Proteinosis-deep-research-claude_code.md)
  used as leads only; every PMID, snippet and ontology term was independently
  verified against PubMed/PMC and OAK. The deep-research report mislabelled two
  trial citations (it attached NEJMoa1816216 to IMPALA and NEJMoa1913590 to a
  sargramostim trial), so trial identities were re-derived from PubMed:
  PMID:32897035 is IMPALA (molgramostim, NEJM 2020), PMID:40834301 is IMPALA-2
  (phase 3, NEJM 2025), and PMID:20167854 is the Japanese inhaled sargramostim
  phase II trial. No GeneReviews chapter covers autoimmune PAP, which is
  expected for a non-Mendelian acquired disease.


  Publication-readiness review (2026-08-05). Gaps closed against the repo's own
  QC metrics rather than by free-form expansion: the `classifications` block was
  absent; pathograph phenotype connectivity was 50% (7/14) and causal-gene
  wiring 0% (HLA-DRB1 sat in `genetic` without reaching a mechanism node); the
  `imaging_findings`, `animal_models` and `datasets` blocks were absent; two
  treatments (plasmapheresis, lung transplantation) carried no evidence; and the
  IMPALA trial the entry already cited was not curated as a `clinical_trials`
  record. Most of the new evidence came from the full text of PMID:35227171,
  which is cached in full rather than abstract-only, so the natural-history data
  (survival curve, spontaneous resolution, cause of death) and the negative
  recommendation on plasmapheresis are now quotable. Connectivity is now 87%
  (13/15); the two remaining unconnected phenotypes are deliberate - chest pain
  has no asserted mechanistic route in the sources, and digital clubbing is
  curated as a REFUTE negative that must not be given a causal in-edge.
  GSE153957 was verified against GEO and its publication (PMID:33820876)
  independently fetched; NCT02702180 was read out of the cached IMPALA report
  rather than assumed.

📚

References & Deep Research

References

3

PMID:35227171

Autoimmune Pulmonary Alveolar Proteinosis.

No top-level findings curated for this source.

PMID:30846703

Pulmonary alveolar proteinosis.

No top-level findings curated for this source.

PMID:14695413

Pulmonary alveolar proteinosis.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Autoimmune Pulmonary Alveolar Proteinosis (aPAP): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 64 citations 2026-08-01T23:56:52.941764

Autoimmune Pulmonary Alveolar Proteinosis (aPAP): Comprehensive Research Report

1. Disease Information

Overview: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare diffuse lung disease characterized by accumulation of surfactant-derived lipoproteinaceous material within alveoli and terminal bronchioles, caused by circulating neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). It accounts for approximately 90% of all pulmonary alveolar proteinosis (PAP) cases, making it the dominant clinical form of the broader PAP syndrome ATS Journal, Trapnell et al.. The disease is now understood as "a myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency" driven by autoantibody neutralization of GM-CSF (Current Pulmonology Reports 2024).

Key identifiers: - Orphanet: ORPHA:747 (Orphanet; OLS/ORDO) - MONDO: MONDO:0012579 (autoimmune pulmonary alveolar proteinosis) — distinct from MONDO:0012580 (hereditary pulmonary alveolar proteinosis) (Monarch Initiative) - OMIM: 610910 — "Pulmonary Alveolar Proteinosis, Acquired" (OMIM) - ICD-10-CM: J84.01 — Alveolar proteinosis (ICD10Data) - GARD (NIH): Disease ID 7499 (GARD) — aggregates Orphanet, OMIM, and MONDO data

Synonyms: Acquired pulmonary alveolar proteinosis; primary autoimmune PAP; idiopathic PAP (older term, largely superseded now that the GM-CSF autoantibody mechanism is understood); aPAP.

Data derivation: Most published knowledge derives from aggregated disease-level resources — national/regional patient registries (notably Japanese nationwide cohorts), single- and multi-center case series, and a handful of randomized controlled/phase 3 trials (IMPALA, IMPALA-2) — rather than large-scale individual-level EHR mining, reflecting the disease's rarity.

2. Etiology

Primary cause: aPAP is caused by polyclonal, high-titer, neutralizing IgG autoantibodies directed against GM-CSF. These autoantibodies bind and block GM-CSF from engaging its receptor (CSF2RA/CSF2RB) on alveolar macrophages and other myeloid cells, abrogating GM-CSF-dependent alveolar macrophage terminal differentiation and surfactant catabolism (Nature Communications 2015; PMC8647160). Recent work shows that total autoantibody titer does not correlate with disease severity; rather, epitope specificity and binding affinity are the key determinants of pathogenicity — a 2026 Nature Communications study characterized "affinity- and epitope-dependent pathogenicity of GM-CSF autoantibodies" (Nature Communications 2026).

Genetic risk factors: A genome-wide association study of 198 Japanese aPAP patients versus 395 controls identified two independent MHC risk loci: - HLA-DRB1*08:03 (OR 5.2) — also associated with higher anti-GM-CSF antibody titers - HLA-DPβ1 epitope (OR 0.28, protective) (Nature Communications 2021, "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis"; PMC7884840).

However, this HLA association has not been consistently replicated: a separate study of 41 aPAP patients versus 1,000 ethnic-matched controls found no HLA association (PLOS ONE; PMC6405167), suggesting population-specific or study-power-dependent genetic architecture.

Environmental/lifestyle risk factors: - Age and cigarette smoking are established risk factors for aPAP; smoking and dust inhalation are hypothesized to accelerate onset (ATS Journal review). A case report documented fluctuating radiographic disease burden tracking with cigarette smoke exposure (PMC7170098). - Occupational/inhalational exposures (silica, aluminum dust) are more clearly linked to secondary PAP than to autoimmune PAP; in a German cohort, silica dust exposure was reported in 21% and aluminum dust in 18% of cases, though causal attribution to the autoimmune subtype specifically remains uncertain. - Vaping/e-cigarette exposure and vitamin E acetate have been reported in individual case reports of aPAP (PMC8521389).

Gene-environment interactions: The prevailing model is a "two-hit" framework — an HLA-conferred (or otherwise genetically determined) predisposition to break tolerance to GM-CSF, combined with an environmental trigger (inhalational exposure, infection, or another autoimmune process) that precipitates autoantibody production. This remains incompletely characterized mechanistically and is an area of active investigation.

Protective factors: No specific protective genetic or environmental factors are firmly established beyond the HLA-DPβ1 protective epitope noted above.

3. Phenotypes

Symptom onset and course: Onset is typically insidious/gradual in patients aged 20–50 years, though pediatric and elderly-onset cases occur (Orphanet; GARD).

Phenotype	Frequency/notes	Suggested HPO term
Dyspnea (exertional progressing to rest)	Most common presenting symptom	HP:0002094 (Dyspnea)
Cough (dry or with whitish/frothy sputum)	Second most common symptom	HP:0012735 (Cough)
Fatigue	Common	HP:0012378 (Fatigue)
Weight loss	Occurs with disease progression	HP:0001824 (Weight loss)
Chest pain	Reported	HP:0100749 (Chest pain)
Low-grade fever	Reported, especially with superimposed infection	HP:0001945 (Fever)
Hemoptysis	Uncommon	HP:0002105 (Hemoptysis)
Crackles on auscultation	Fine bibasilar crackles common	HP:0030830 (Crackles)
Hypoxemia	Progressive with disease severity	HP:0012418 (Hypoxemia)
Cyanosis	Late/severe disease	HP:0000961 (Cyanosis)
Digital clubbing	Uncommon/atypical — its presence should prompt consideration of alternative or complicating diagnoses (e.g., fibrosis)	HP:0100759 (Clubbing)
Asymptomatic/incidental finding	Up to ~30% identified incidentally on imaging	—

Source: GARD, NORD, Cleveland Clinic, PMC12180566 "Dyspnea and Deception".

Severity and progression: Disease course is heterogeneous — ranging from spontaneous remission, to stable/indolent disease, to progressive respiratory failure. Severity correlates with radiographic burden (crazy-paving extent on HRCT), gas exchange parameters (PaO2, A-a gradient), and DLCO. Chinese multi-center cohorts have developed composite severity/prognosis scores (DSS, SPSP, and an updated SPSPII incorporating smoking status, symptoms, PaO2, %-predicted DLCO, and HRCT score) that outperform earlier single-parameter staging (PMC9941621).

Quality of life impact: Progressive dyspnea and fatigue substantially impair daily functioning; disease-specific QoL instruments are not well standardized in aPAP, and most QoL data come from case series rather than validated instruments (EQ-5D/SF-36 data are sparse in the primary literature).

4. Genetic/Molecular Information

Unlike hereditary PAP, autoimmune PAP is not a Mendelian genetic disease — no single causal gene mutation is required. However:

HLA-DRB1*08:03 and HLA-DPβ1 are associated risk/protective MHC alleles in at least one large Japanese GWAS (see Etiology, above) (Nature Communications 2021).
MUC1 gene polymorphisms are associated with serum KL-6 levels and degree of pulmonary dysfunction in PAP, acting as a modifier of the biomarker/severity relationship rather than a causal driver (PMC4841967).
The causal molecular lesion is autoantibody-mediated functional GM-CSF deficiency rather than a structural gene defect — functionally analogous to but molecularly distinct from hereditary PAP (CSF2RA/CSF2RB loss-of-function mutations; HGNC:2435/HGNC:2436) and to the original description of PAP as a state where "GM-CSF gene expression is normal but protein release is absent" in some contexts (PubMed 9412586).
Somatic vs. germline: The autoantibodies are a somatically generated (B-cell/plasma-cell derived), polyclonal humoral immune product — not a germline or somatic DNA lesion.
Relevant gene/protein identifiers: CSF2 (GM-CSF ligand, HGNC:2434), CSF2RA (HGNC:2435), CSF2RB (HGNC:2436), PPARG (HGNC:9236), ABCG1 (HGNC:14638), PU.1/SPI1 (HGNC:11241) — all implicated in the downstream signaling/lipid-clearance axis (see Mechanism, below).

Epigenetics: No well-established disease-specific epigenetic signature has been reported in the primary literature reviewed; this remains an evidence gap.

5. Environmental Information

Toxin/occupational exposures: Silica and aluminum dust are the most frequently implicated inhalational hazards in cohorts that include PAP broadly, though their causal role is more firmly established for secondary PAP than for the autoimmune subtype specifically.
Smoking: An established accelerant/risk factor, with case evidence of disease activity fluctuating with smoking exposure (PMC7170098).
Vaping/inhalant substance use: Case reports link vaping and chronic inhalant/substance abuse to PAP presentations, including one describing vitamin E-acetate-positive BAL fluid in a vaping-associated aPAP case (PMC8521389; PMC5828087).
Infectious agents: Infections are not established as causal triggers of aPAP itself, but the GM-CSF-autoantibody state independently and bidirectionally interacts with infection risk (see Mechanism/Diagnostics — opportunistic infection section). Notably, GM-CSF autoantibodies have been identified in patients presenting primarily with disseminated nocardiosis, cryptococcal meningitis, and disseminated mycobacterial infection, sometimes in the absence of overt PAP (PMC9552154; JACI 2024; J Clin Immunol 2024).

6. Mechanism / Pathophysiology

Causal chain (trigger → clinical manifestation):

Trigger/upstream: Loss of immune tolerance to GM-CSF (influenced by HLA-DRB1*08:03 and possibly environmental co-factors) → polyclonal B-cell production of high-affinity, epitope-specific neutralizing anti-GM-CSF IgG autoantibodies (Nat Commun 2026).
Molecular pathway disruption: Circulating autoantibodies bind and neutralize/clear serum and local GM-CSF, preventing engagement of the GM-CSF receptor (CSF2RA/CSF2RB heterodimer) on alveolar macrophages. GM-CSF receptor signaling normally operates through two concentration-dependent branches: at low ligand concentration, phosphorylation of receptor serine585 couples to 14-3-3/PI3K/Akt signaling; at high concentration, phosphorylation of tyrosine577 couples to STAT5- and Shc-dependent pathways driving macrophage survival, activation, and proliferation (review, PMC11241585).
Cellular consequence: Loss of GM-CSF signaling impairs alveolar macrophage terminal differentiation, in particular failure to upregulate PU.1 (SPI1) and PPAR-γ, which are required for the GM-CSF–PU.1–PPARγ–ABCG1 axis governing cholesterol/lipid efflux and surfactant lipid catabolism in alveolar macrophages (PMC8647160; ATS Journal mechanistic review). Disruption of this axis is described as "dysregulation of cholesterol export within alveolar macrophages," where cholesterol accumulation impedes surfactant clearance (Current Pulmonology Reports 2024).
Tissue-level consequence: Progressive accumulation of PAS-positive, lipid-rich (oil-red-O-positive) surfactant material within alveolar macrophages and free within alveolar spaces → alveolar filling, impaired gas exchange, and the radiographic "crazy-paving" pattern.
Downstream/organism-level: Restrictive-to-mixed physiology, hypoxemia, and in a subset of patients, secondary pulmonary fibrosis — hypothesized to result from chronic retained lipoproteinaceous material, silica co-exposure, and/or superimposed infection causing epithelial injury (ERS 2024, "Pulmonary fibrosis in patients with autoimmune pulmonary alveolar proteinosis"). Hyaluronan has also been implicated in the fibrogenic cascade in aPAP-associated fibrosis (PMC12440733).

Immune system involvement: aPAP is now conceptually framed as a combined autoimmune disease + acquired innate immunodeficiency: the same autoantibodies that drive alveolar macrophage dysfunction also impair GM-CSF-dependent functions in circulating neutrophils (phagocytosis, chemotaxis, microbicidal activity) and other myeloid cells, producing a state of susceptibility to opportunistic infection independent of overt lung disease severity (PMC8647160).

Cell types involved (Cell Ontology suggestions): - Alveolar macrophage — CL:0000583 - Type II pneumocyte (surfactant-producing) — CL:0002063 - Neutrophil — CL:0000775 - Plasma cell (autoantibody-producing) — CL:0000786

GO biological process suggestions: - Surfactant homeostasis — GO:0043129 - Macrophage differentiation — GO:0030225 - Cholesterol efflux — GO:0033344 - Regulation of phagocytosis — GO:0050764 - Humoral immune response — GO:0006959

Molecular profiling: Serum and BAL proteomic/biomarker studies (KL-6, SP-A, SP-D, CYFRA21-1, CEA, LDH) are the primary "omics" layer characterized to date (see Diagnostics, below); large-scale transcriptomic/single-cell atlases specific to aPAP alveolar macrophages are limited in the literature surfaced here and represent a research gap.

7. Anatomical Structures Affected

Primary organ: Lung (respiratory system), specifically the alveoli and terminal bronchioles — UBERON:0002048 (lung); UBERON:0002299 (alveolar system); UBERON:0001991 (pulmonary alveolus)
Secondary/systemic involvement: Because GM-CSF autoantibodies impair neutrophil function systemically, extrapulmonary sites of opportunistic infection occur — notably CNS (Nocardia and Cryptococcal CNS infection) and disseminated mycobacterial disease, representing a secondary/complication-driven organ involvement rather than primary pathophysiology.
Tissue/cell level: Alveolar epithelium (type II pneumocytes, surfactant source) and alveolar macrophages (the primary dysfunctional effector cell) — Cell Ontology terms above.
Subcellular level: Macrophage lysosomes/phagolysosomes (site of impaired surfactant lipid catabolism) — GO:0005764 (lysosome); mitochondria and lipid droplets in lipid-laden ("foamy") macrophages.
Localization/laterality: Diffuse, typically bilateral, often basal-predominant or perihilar "bat-wing" distribution on imaging; classically patchy with sharp demarcation between affected and unaffected lung ("geographic" distribution).

8. Temporal Development

Onset: Typically insidious in adults 20–50 years old; pediatric-onset and elderly-onset (including cases in the 70s–80s) reported, the latter sometimes overlapping in presentation with hereditary PAP work-up.
Progression: Variable — a substantial minority follow an indolent/stable course, some undergo spontaneous remission, and others progress to hypoxemic respiratory failure. Disease severity scoring systems (DSS, SPSP, updated SPSPII) stratify HRCT extent, PaO2, and DLCO to track progression (PMC9941621).
Complications over time: Pulmonary fibrosis develops in a variable proportion of patients over years of follow-up — reported rates range widely (1.4% with severe fibrotic respiratory failure in a 223-patient Japanese cohort, versus 26% with any fibrosis on CT at median 3.6 years follow-up in another cohort), reflecting differences in fibrosis definition/detection threshold across studies (ERS 2024).
Remission patterns: Both spontaneous and treatment-induced (post-WLL, post-GM-CSF therapy) remission are documented; relapse can occur, particularly if autoantibody titers/affinity remain elevated.

9. Inheritance and Population

Inheritance pattern: Not Mendelian — aPAP is an acquired autoimmune disease, though HLA-linked genetic susceptibility modifies risk (see Etiology).
Prevalence: Estimates vary substantially by region and case-ascertainment method:
Japan: ~1/38,000 (higher due to a national registry and greater case-finding) (NORD)
United States: ~1/150,000 (likely an underestimate due to underdiagnosis)
A separate cross-national estimate: PAP prevalence 6.87 ± 0.33 per million population overall, similar between sexes, increasing with age (Orphanet J Rare Dis 2018; PMC6069872)
A 2025 Japanese administrative claims database study provides updated national epidemiology (PubMed 39872388)
Sex ratio: Historically described with male predominance, though more recent population-level data suggest near-equal sex distribution once ascertainment bias is accounted for.
Age distribution: Peak presentation 20–50 years; pediatric and elderly-onset cases occur but are less common.
Founder effects/consanguinity/carrier frequency: Not applicable — these concepts apply to the hereditary (CSF2RA/CSF2RB) form, not autoimmune PAP.
Geographic distribution: No strong endemic geographic clustering reported beyond registry-driven detection differences (Japan's higher reported prevalence reflects a mature national PAP registry rather than a true regional excess).

10. Diagnostics

Imaging: High-resolution CT (HRCT) shows the classic "crazy-paving" pattern — ground-glass opacities with superimposed interlobular septal thickening — often with sharp geographic demarcation between affected and normal parenchyma (AJR; PMC5354367). Quantitative CT scoring correlates with pulmonary function test results.

Bronchoalveolar lavage (BAL): Usually diagnostic without biopsy. Lavage fluid is grossly milky/opaque; cytology shows large, foamy alveolar macrophages and extracellular eosinophilic proteinaceous material that is PAS-positive and Alcian-blue-negative, with oil-red-O-positive lipid content (StatPearls; Hindawi CRJ 2016).

Serologic diagnosis: Elevated serum anti-GM-CSF autoantibody titer (typically measured by ELISA) is considered diagnostic/confirmatory for the autoimmune subtype and distinguishes it from hereditary and secondary PAP.

Serum biomarkers (disease activity/monitoring): - KL-6 (high-molecular-weight MUC1 mucin) — elevated in serum and BAL in most aPAP patients, correlates with disease activity, decreases post-WLL, and is a validated predictor of outcome/mortality (Orphanet J Rare Dis 2013; PMC3629718). MUC1 polymorphisms modify baseline KL-6 levels (PMC4841967). - SP-A and SP-D (surfactant proteins) — elevated; SP-A/SP-D show transient post-WLL rises distinct from KL-6's decline pattern. - CYFRA21-1 — reported as a more sensitive severity biomarker than some traditional markers (PMC8725332). - LDH, CEA, CA15-3, NSE — correlate positively with disease severity score and A-a gradient in Chinese cohort studies.

Genetic/molecular testing: Not required for diagnosis of the autoimmune form per se, but CSF2RA/CSF2RB sequencing is used to exclude hereditary PAP, particularly in atypical-age presentations or when anti-GM-CSF antibodies are unexpectedly negative.

Suggested LOINC/SNOMED considerations: BAL cytology PAS stain, serum KL-6 assay, and anti-GM-CSF antibody assay are the key laboratory studies; specific LOINC codes should be confirmed against local lab compendia at curation time.

Differential diagnosis: Hereditary PAP (CSF2RA/CSF2RB mutation, GM-CSF-antibody-negative, earlier onset), secondary PAP (hematologic malignancy, immunodeficiency, chronic infection, pneumotoxic exposure — macrophage number/function reduced by an underlying condition rather than autoantibody-mediated), other interstitial lung diseases with ground-glass/crazy-paving patterns (e.g., NSIP, organizing pneumonia, lipoid pneumonia, PJP pneumonia).

Complications requiring diagnostic vigilance: Because of the associated innate immune deficiency, clinicians are advised to maintain a high index of suspicion for opportunistic infection (Nocardia, Cryptococcus, nontuberculous/tuberculous mycobacteria) in patients with elevated GM-CSF autoantibodies, even in the absence of classic PAP radiographic findings (Open Forum Infect Dis 2022).

11. Outcome/Prognosis

Survival: Approximately 80% five-year survival with treatment (GARD/NORD estimates). Disease course ranges from spontaneous remission through chronic stable disease to death from respiratory failure or secondary infection.
Mortality drivers: Progressive hypoxemic respiratory failure; secondary pulmonary fibrosis (a "rare but potentially life-threatening complication," with severe fibrotic respiratory failure in ~1.4% of a 223-patient Japanese cohort); opportunistic infection (disseminated nocardiosis, cryptococcal meningitis, mycobacterial disease) related to the GM-CSF-antibody-driven innate immune defect.
Prognostic biomarkers: Serum KL-6 is a validated predictor of outcome (PMC3629718); composite severity scores (DSS/SPSP/SPSPII incorporating HRCT score, PaO2, %-predicted DLCO, smoking status) predict prognosis and treatment response in Chinese multi-center cohorts (PMC9941621).
Recovery potential: WLL and GM-CSF augmentation therapy substantially improve gas exchange and reduce disease burden; complete resolution occurs in only ~30% with WLL alone, improved further by combination with inhaled GM-CSF therapy.
COVID-19 interaction: A single-center study specifically examined outcomes of COVID-19 infection in aPAP patients, relevant given the innate immune deficiency component of the disease (PMC10638736).

12. Treatment

First-line — Whole Lung Lavage (WLL): Remains the standard of care; performed under general anesthesia, sequential lavage of each lung with large-volume saline to mechanically remove accumulated surfactant material. WLL alone achieves complete resolution in only ~30% of patients (CHEST/journal.chestnet.org). NCIT suggestion: therapeutic bronchoalveolar lavage procedure (closest available NCIT clinical-intervention term should be verified via OAK, e.g. under Therapeutic Procedure NCIT:C49236).

GM-CSF augmentation therapy (pharmacotherapy, pathogenesis-driven): - Inhaled sargramostim (recombinant human GM-CSF) — restores alveolar macrophage GM-CSF signaling/function locally, bypassing circulating neutralizing antibodies to some degree. A phase II randomized trial showed inhaled sargramostim following WLL reduced need for repeat WLL, improved lung function, and was safe and more effective than WLL alone (PubMed 37973175; NEJM 2019). - Inhaled molgramostim (recombinant GM-CSF, Savara Inc.) — the most advanced pharmacotherapy in development: - Phase 2/3 IMPALA trial: NEJM 2020 (NEJM) - Phase 3 IMPALA-2 trial (164 patients, 300 μg once daily × 48 weeks): significantly greater improvement in DLCO (hemoglobin-adjusted, % predicted at week 24, primary endpoint) versus placebo (NEJM 2025; PubMed 40834301; plain-language summary) - Regulatory status (as of the search date): BLA (brand name Molbreevi) submitted to FDA December 2025; PDUFA target action date extended to November 22, 2026; an FDA-permitted Early Access Program has been running since September 2024 (Drugs.com; CHEST Physician). Not yet FDA-approved at time of this report.

Refractory disease (per ERS treatment sequencing): 1. WLL 2. Inhaled GM-CSF 3. Rituximab (anti-CD20 B-cell depletion, typically 1000 mg × 2 doses two weeks apart) — reduces anti-GM-CSF titers, improves oxygenation, decreases WLL frequency 4. Plasmapheresis — case-level evidence of reduced anti-GM-CSF antibody levels (e.g., 24.8 → 2.7 mcg/mL after a 5-day protocol) correlating with reduced WLL need, improved DLCO, and symptomatic benefit, though responses are inconsistent across reported cases; some patients remain refractory to both rituximab and plasmapheresis despite antibody reduction (PMC8818429; PubMed 25557091) (Drugs journal 2025, pharmacotherapy review)

Advanced/last-resort: Lung transplantation for suitable patients with severe disease refractory to all other therapies; notably, PAP recurrence post-transplant has been reported (PMC7199162).

Suggested NCIT terms: - Rituximab — NCIT:C1197 (verify via OAK) - Plasmapheresis — closest NCIT therapeutic-procedure term (verify) - Lung transplantation — NCIT:C15289 (Organ Transplantation) - Pharmacotherapy (generic, for GM-CSF biologics) — NCIT:C15986, with therapeutic_agent bound to sargramostim/molgramostim (CHEBI or NCIT drug term — verify exact identifiers via OAK before curation)

Emerging/experimental: Pulmonary macrophage transplantation has shown efficacy in preclinical (murine Csf2ra−/−) models of hereditary PAP and is conceptually relevant as a future cell-therapy direction, though this is currently demonstrated in the hereditary rather than autoimmune model system.

13. Prevention

No established primary prevention (e.g., vaccination) exists for aPAP, as the autoimmune trigger is not fully characterized. Reasonable extrapolated measures based on identified risk factors: - Smoking cessation counseling — since smoking is an established risk/aggravating factor - Avoidance of inhalational occupational hazards (silica, aluminum dust) where feasible, particularly relevant to reducing secondary-PAP risk and possibly aPAP severity/fibrosis progression - Secondary prevention/surveillance: Given the innate immune deficiency, clinicians monitoring known aPAP or GM-CSF-autoantibody-positive patients should maintain heightened surveillance for opportunistic infection (Nocardia, Cryptococcus, mycobacteria), enabling earlier detection and treatment of disseminated infection. - Genetic counseling: Not applicable in the classic sense (non-Mendelian), though differentiating from hereditary PAP is relevant for family counseling when hereditary PAP is in the differential.

14. Other Species / Natural Disease

Naturally occurring autoimmune PAP driven by spontaneous anti-GM-CSF autoantibodies has not been robustly documented as a natural veterinary disease in the literature surfaced by this search; PAP-like presentations in animals are more typically studied via engineered genetic models (below) rather than spontaneous autoimmune disease.
Comparative biology of the GM-CSF/alveolar macrophage axis is well conserved across mammals, underpinning the utility of mouse models (below).

15. Model Organisms

GM-CSF-deficient (Csf2−/−) mice: The original and foundational model. GM-CSF knockout mice spontaneously develop a PAP-like phenotype due to defective surfactant clearance from failure of alveolar macrophage terminal differentiation, closely paralleling human PAP pathology, with impaired innate immunity to pulmonary pathogens as a shared feature (BMC Immunology 2013, "mixed M1/M2 phenotypes").

Csf2ra−/− mice (hereditary PAP model, mechanistically relevant to the shared downstream pathway): A more recent, refined murine model in which macrophages cannot bind or signal through GM-CSF, exhibiting functional defects in phagocytosis, cholesterol clearance, and surfactant clearance; mice develop time-dependent, progressive lung disease closely paralleling human hereditary PAP clinical, physiological, histopathological, biochemical, and biomarker features (Am J Physiol Lung Cell Mol Physiol 2021). This model has been used to test pulmonary macrophage transplantation (PMT) without myeloablation, achieving long-term engraftment and durable restoration of GM-CSF responsiveness over 6 months of follow-up.

Humanized IL-3/GM-CSF knock-in mice: Engineered to express human IL-3/GM-CSF, supporting human alveolar macrophage development and human immune responses in the lung — a translational bridge model for studying human myeloid biology in vivo (PNAS 2011; PMC3038773).

Model limitations: None of these genetic models fully recapitulates the autoimmune (autoantibody-driven, HLA-associated) etiology of human aPAP — they model the shared downstream GM-CSF-signaling-loss pathophysiology rather than the upstream autoimmune breakdown of tolerance. A true autoantibody-mediated aPAP model (e.g., passive transfer of anti-GM-CSF antibodies, or an induced-autoimmunity model) was not identified as a well-established standard model in this search and represents a documented modeling gap — relevant to a HUMAN_MODEL_MISMATCH framing if curated into a mechanistic knowledge base, since model organisms recapitulate the surfactant-clearance/macrophage-dysfunction phenotype but not the autoimmune trigger itself.

Resources: MGI (Mouse Genome Informatics) for Csf2/Csf2ra/Csf2rb knockout allele records; IMPC/KOMP for conditional/knockout mouse line availability.

Summary of Suggested Ontology Terms for Curation

Category	Term
Disease	MONDO:0012579 (autoimmune PAP); ORPHA:747; OMIM:610910; ICD-10-CM:J84.01
Related/differential disease	MONDO:0012580 (hereditary PAP)
Causal gene/protein (ligand)	CSF2 / GM-CSF, HGNC:2434
Receptor genes	CSF2RA (HGNC:2435), CSF2RB (HGNC:2436)
Downstream TFs/transporters	SPI1/PU.1 (HGNC:11241), PPARG (HGNC:9236), ABCG1 (HGNC:14638)
Key phenotype (HP)	Dyspnea HP:0002094; Cough HP:0012735; Hypoxemia HP:0012418; Crackles HP:0030830
Key cell types (CL)	Alveolar macrophage CL:0000583; Type II pneumocyte CL:0002063; Neutrophil CL:0000775
Key anatomy (UBERON)	Lung UBERON:0002048; Pulmonary alveolus UBERON:0001991
Key GO processes	Surfactant homeostasis GO:0043129; Macrophage differentiation GO:0030225; Cholesterol efflux GO:0033344
Treatments (NCIT, verify via OAK before use)	Pharmacotherapy NCIT:C15986; Organ Transplantation NCIT:C15289

(All ontology term IDs above should be independently verified against the live OAK adapters before insertion into any dismech YAML entry, per project SOP — this report is a research input, not pre-validated curation content.)

Notes on Evidence Gaps

No MONDO/Orphanet-listed formal ICD-11 mapping was independently confirmed in this pass (ICD-10-CM J84.01 was confirmed; the ICD-11 equivalent should be separately verified).
Precise 5-year survival and mortality figures come from patient-advocacy/aggregator summaries (NORD/GARD) rather than a single primary epidemiological study with a directly quotable abstract sentence — a primary-source survival curve (e.g., from a national registry cohort paper) should be sourced and quoted verbatim before use as curated evidence.
A dedicated autoantibody-mediated (rather than genetic-knockout) mouse/model-organism system for aPAP was not identified; this is a genuine translational gap, not a search omission.
HLA association findings are population-inconsistent (positive in one Japanese GWAS, negative in another cohort) — this contradiction should be preserved as a KNOWLEDGE_GAP/nuanced etiology claim rather than flattened to a single "HLA-DRB1*08:03 causes aPAP" statement.

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Deep Research

Autoimmune Pulmonary Alveolar Proteinosis (aPAP): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Suggested Ontology Terms for Curation

Notes on Evidence Gaps