The molecular basis of pulmonary alveolar proteinosis

Abstract

Pulmonary alveolar proteinosis (PAP) comprises a heterogenous group of diseases characterized by abnormal surfactant accumulation resulting in respiratory insufficiency, and defects in alveolar macrophage-and neutrophil-mediated host defense. Basic, clinical and translational research over the past two decades have raised PAP from obscurity, identifying the molecular pathogenesis in over 90% of cases as a spectrum of diseases involving the disruption of GM-CSF signaling. Autoimmune PAP represents the vast majority of cases and is caused by neutralizing GM-CSF autoantibodies. Genetic mutations that disrupt GM-CSF receptor signaling comprise a rare form of hereditary PAP. In both autoimmune and hereditary PAP, loss of GM-CSF signaling blocks the terminal differentiation of alveolar macrophages in the lungs impairing the ability of alveolar macrophages to catabolize surfactant and to perform many host defense functions. Secondary PAP occurs in a variety of clinical diseases that presumedly cause the syndrome by reducing the numbers or functions of alveolar macrophages, thereby impairing alveolar macrophage-mediated pulmonary surfactant clearance. A similar phenotype occurs in mice deficient in the production of GM-CSF or GM-CSF receptors. PAP and related research has uncovered a critical and emerging role for GM-CSF in the regulation of pulmonary surfactant homeostasis, lung host defense, and systemic immunity.

Elevated Serum Anti-GM-CSF Antibodies before the Onset of Autoimmune Pulmonary Alveolar Proteinosis in a Patient with Sarcoidosis and Systemic Sclerosis

“…The serum autoantibodies against GM-CSF are normally present in healthy people at low levels, and more than 99% of the GM-CSF were bound and neutralized by the GM-CSF autoantibodies (Uchida et al 2009). In patients with autoimmune PAP, the levels of serum anti-GM-CSF antibodies increase beyond the critical threshold (Carey and Trapnell 2010). Plasma GM-CSF levels were elevated from patients with localized scleroderma (Torok et al 2015).…”

“…Secondary PAP is caused by macrophage dysfunction due to relative deficiency of GM-CSF that occurs as a consequence of hematological disorders, inhalation injuries, infection, autoimmune diseases, or pharmacologic immunosuppression (Carey and Trapnell 2010). If we did not measure the concentration of serum anti-GM-CSF antibodies, we might diagnose this patient as having secondary PAP, because of the underlying autoimmune disease and usage of immunosuppressant therapy.…”

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

“…Moreover, administration of GM-CSF ameliorates IPAP (18). Animals or humans that lack functional genes encoding either GM-CSF or the GM-CSF receptor have pulmonary alveolar proteinosis (19).…”

Tos e hipoxemia como manifestación clínica de la proteinosis alveolar. Reporte de caso clínico

“…Fenómeno de autoinmunidad con producción de anticuerpos dirigidos contra el GM-CSF. [5][6][7][8] • Secundarias: En pacientes con enfermedades hematológicas, inmunodeficiencias, infecciones crónicas o por exposición a polvos inorgá-nicos y humos tóxicos. Se manifiesta con tos seca, disnea progresiva, taquipnea, hipoxemia persistente y mal progreso de peso; estos dos últimos son más frecuentemente en niños, síntomas que se evidencian en nuestra paciente.…”