The presence of autoimmune antibodies in pulmonary alveolar proteinosis does not necessarily imply idiopathic disease

Abstract

The discovery of the role of granulocyte–macrophage colony-stimulating factor autoantibodies (GMAb) was a breakthrough in the understanding of the pathogenesis of pulmonary alveolar proteinosis (PAP). As described in the Review by Kumar and colleagues,1Kumar A Abdelmalak B Inoue Y Culver DA Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach.Lancet Respir Med. 2018; 6: 554-565Summary Full Text Full Text PDF PubMed Scopus (83) Google Scholar it led to the classification of PAP into hereditary forms, autoimmune PAP (defined by the presence of GMAb), and secondary PAP (mainly caused by inhalational exposure or haematological, infectious, or autoimmune disorders). Although this classification seems to be supported by the absence of GMAb in cohorts of patients with secondary PAP, several authors have highlighted that these cohorts only included cases secondary to various comorbidities, and no exposure-related cases.2Cummings KJ Donat WE Ettensohn DB Roggli VL Ingram P Kreiss K Pulmonary alveolar proteinosis in workers at an indium processing facility.Am J Respir Crit Care Med. 2010; 181: 458-464Crossref PubMed Scopus (135) Google Scholar, 3Xiao YL Xu KF Li Y et al.Occupational inhalational exposure and serum GM-CSF autoantibody in pulmonary alveolar proteinosis.Occup Environ Med. 2015; 72: 504-512Crossref PubMed Scopus (11) Google Scholar Therefore, the implicit claim that autoimmune (GMAb-positive) PAP is not related to exogenous exposures is not supported by evidence. Cummings and colleagues2Cummings KJ Donat WE Ettensohn DB Roggli VL Ingram P Kreiss K Pulmonary alveolar proteinosis in workers at an indium processing facility.Am J Respir Crit Care Med. 2010; 181: 458-464Crossref PubMed Scopus (135) Google Scholar provided a good example of detectable GMAb in a patient with PAP related to occupational indium-tin oxide exposure. 26–54% of patients with autoimmune PAP have a history of inhalational exposure.3Xiao YL Xu KF Li Y et al.Occupational inhalational exposure and serum GM-CSF autoantibody in pulmonary alveolar proteinosis.Occup Environ Med. 2015; 72: 504-512Crossref PubMed Scopus (11) Google Scholar, 4Inoue Y Trapnell BC Tazawa R et al.Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan.Am J Respir Crit Care Med. 2008; 177: 752-762Crossref PubMed Scopus (323) Google Scholar Moreover, Xiao and colleagues3Xiao YL Xu KF Li Y et al.Occupational inhalational exposure and serum GM-CSF autoantibody in pulmonary alveolar proteinosis.Occup Environ Med. 2015; 72: 504-512Crossref PubMed Scopus (11) Google Scholar showed that, in patients with autoimmune PAP, the prevalence of current exposure (32%), but not past exposure, was significantly higher than that in hospital controls (5%).3Xiao YL Xu KF Li Y et al.Occupational inhalational exposure and serum GM-CSF autoantibody in pulmonary alveolar proteinosis.Occup Environ Med. 2015; 72: 504-512Crossref PubMed Scopus (11) Google Scholar In a 1978 study by McEuen and Abraham,5McEuen DD Abraham JL Particulate concentrations in pulmonary alveolar proteinosis.Environ Res. 1978; 17: 334-339Crossref PubMed Scopus (19) Google Scholar 78% of PAP cases of unknown origin had significantly higher alveolar particle counts than those of control patients with PAP secondary to infection.5McEuen DD Abraham JL Particulate concentrations in pulmonary alveolar proteinosis.Environ Res. 1978; 17: 334-339Crossref PubMed Scopus (19) Google Scholar GMAb are found in 90–95% of adult PAP cases, suggesting that inhaled agents might cause PAP not only by direct toxic effects on alveolar macrophages but also by triggering an autoimmune response.2Cummings KJ Donat WE Ettensohn DB Roggli VL Ingram P Kreiss K Pulmonary alveolar proteinosis in workers at an indium processing facility.Am J Respir Crit Care Med. 2010; 181: 458-464Crossref PubMed Scopus (135) Google Scholar The concept of inhalational exposures causing or triggering autoimmune disease is not new. Strong associations have, for example, been shown for silica exposure and scleroderma,6Rubio-Rivas M Moreno R Corbella X Occupational and environmental scleroderma. Systematic review and meta-analysis.Clin Rheumatol. 2017; 36: 569-582Crossref PubMed Scopus (65) Google Scholar indicating that autoimmune is not synonymous with idiopathic. Although the exact role of autoimmunity in the pathophysiology of exposure-related PAP is still unclear, these data suggest that the current classification needs to be revised. Our comments are not of purely academic interest, but have clinical implications: the detection of GMAb in a patient with PAP might lead to the erroneous conclusion that the patient has an idiopathic disorder and thus prevent searching for inhalational exposures. We argue that environmental exposures should be carefully assessed (and discontinued) in patients with PAP, regardless of the presence of GMAb. We declare no competing interests. Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approachPulmonary alveolar proteinosis (PAP) is a diffuse lung disease that results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages due to abnormal surfactant homoeostasis. Identification of the granulocyte–macrophage colony-stimulating factor (GM-CSF) as an indispensable mediator of macrophage maturation and surfactant catabolism was the key discovery leading to the current understanding of the pathogenesis of most forms of PAP. Impaired GM-CSF bioavailability due to anti-GM-CSF autoimmunity is the cause of approximately 90% of adult PAP cases. Full-Text PDF