Current classification of pulmonary alveolar proteinosis (PAP) syndrome
| Clinical type | Pathogenesis |
|---|---|
| Primary PAP | Disruption of GM-CSF signalling |
| Autoimmune | GM-CSF autoantibodies [7, 8] |
| Hereditary | GM-CSF receptor α/β chain encoding gene mutations [9] |
| Secondary PAP | Reduced alveolar macrophage functions and/or numbers |
| Haematological disorders | Myelodysplastic syndrome [10] Acute lymphatic leukaemia [11] Acute myeloid leukaemia [12, 13] Chronic myeloid leukaemia [14–16] Hairy cell leukaemia [17, 18] Hodgkin's disease [19] Non-Hodgkin's lymphoma [20] Multiple myeloma [20, 21] Essential thrombocythaemia [22] Polycythaemia vera [20] Amyloidosis [23] Fanconi's anaemia [24, 25] GATA 2 deficiency [26, 27] |
| Other malignancies | Adenocarcinoma [28–30] Glioblastoma [25] Melanoma [31] |
| Immune deficiency syndromes | Monoclonal gammopathy [32] Selective IgA deficiency [33] Severe combined immunodeficiency [34] OPAID [35, 36] |
| Chronic inflammatory and autoimmune syndromes | Inflammatory bowel disease [37, 38] Systemic lupus erythematosus [39] Polymyositis and dermatomyositis [40, 41] Rheumatoid arthritis [42] Multiple sclerosis [3] Autoimmune haemolytic anaemia [43] ANCA-associated vasculitis [44] Others: sarcoidosis, hypersensitivity pneumonitis [45, 46] |
| Toxic inhalation syndromes | Inorganic dusts: aluminium, cement, silica, titanium, indium, tin [47–52] Organic dust: sawdust, fertiliser/agricultural dust, bakery flour [53–55] Fumes: synthetic plastic, gasoline [55] Others: varnish, chlorine, petroleum, cleaning products [56, 57] |
| Metabolic disorders | Lysinuric protein intolerance [58–60] |
| Miscellaneous | IgA nephropathy [61] Coeliac disease [62] Lung transplantation [63] |
| Congenital PAP | Impaired surfactant production: |
| SP-B and SP-C mutations | SP-B and SP-C deficiency, abnormal surfactant [64, 65] |
| ABCA3 mutations | Disrupted surfactant homeostasis [66–68] |
| NKX2-1 mutations | Abnormal lung development [69, 70] |
| Niemann–Pick disease type C | Progressive lysosomal disorder [71, 72] |
| FARSB mutation | Impaired tRNA aminoacylation and metabolism of proteins [73] |
| MARS mutation | Loss-of-function defect in a member of the cytosolic multisynthetase complex [74] |
ABCA3: ATP-binding cassette subfamily A member 3; ANCA: antineutrophilic cytoplasmic antibody; FARSB: phenylalanine-transfer RNA synthetase, β-subunit; GM-CSF: granulocyte−macrophage colony-stimulating factor; MARS: methionyl aminoacyl-transfer RNA synthetase; NKX2-1: NK2 homeobox 1; OPAID: OAS1-associated polymorphic autoinflammatory immunodeficiency disorder; SP: surfactant protein.