The Role of GM-CSF Autoantibodies in Infection and Autoimmune Pulmonary Alveolar Proteinosis: A Concise Review

Abstract

Autoantibodies to multiple cytokines have been identified and some, including antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), have been associated with increased susceptibility to infection. High levels of GM-CSF autoantibodies that neutralize signaling cause autoimmune pulmonary alveolar proteinosis (aPAP), an ultrarare autoimmune disease characterized by accumulation of excess surfactant in the alveoli, leading to pulmonary insufficiency. Defective GM-CSF signaling leads to functional deficits in multiple cell types, including macrophages and neutrophils, with impaired phagocytosis and host immune responses against pulmonary and systemic infections. In this article, we review the role of GM-CSF in aPAP pathogenesis and pulmonary homeostasis along with the increased incidence of infections (particularly opportunistic infections). Therefore, recombinant human GM-CSF products may have potential for treatment of aPAP and possibly other infectious and pulmonary diseases due to its pleotropic immunomodulatory actions.

Keywords: Aspergillus; Cryptococcus; Histoplasma; Nocardia; autoantibodies; autoimmune pulmonary alveolar proteinosis; granulocyte-macrophage colony-stimulating factor (GM-CSF); sargramostim.

Figure 1

Macrophage Dysregulation in aPAP. GM-CSF, produced by alveolar epithelial cells type II (AECII) which binds to the GM-CSF receptor on AECII and macrophages, contributes to surfactant homeostasis and host defense against pulmonary microbial infections. Surfactant production is normally balanced by its catabolism by alveolar macrophages. Uptake and efflux of pulmonary surfactant from alveolar macrophages is normally regulated by GM-CSF. The presence of GM-CSF autoantibodies in aPAP interferes with GM-CSF regulation of surfactant, leading to its accumulation in alveoli. Other critical macrophage functions such as antigen presentation, phagocytosis, and Toll-like receptor signaling, are also affected. Additionally, key regulators of phospholipid metabolism such as the transcription factor PU.1 and ABCG1 are modified, leading to altered fatty acid and phospholipid catabolism and changes in amino acid biosynthesis. βc, GM-CSF receptor common β-subunit; GMRα, GM-CSF receptor subunit-α.

Figure 2

Neutrophil Dysregulation in aPAP. GM-CSF normally binds to the GM-CSF receptor, present on the surface of neutrophils (shown here) and alveolar macrophages, to initiate downstream signaling that regulates multiple functions including phagocytosis, bacterial cell adhesion, and oxidative burst. In aPAP, high levels of GM-CSF autoantibodies bind to GM-CSF preventing binding and receptor activation, thus inhibiting receptor signaling and leading to neutrophil and macrophage dysfunction. βc, GM-CSF receptor common β-subunit; GMRα, GM-CSF receptor subunit-α.

Figure 3

Algorithm for Diagnosis of Pulmonary Alveolar Proteinosis (PAP). Patients suspected of having PAP on the basis of clinical history and imaging findings should undergo screening for serum GM-CSF autoantibodies. Elevated autoantibody levels confirm a diagnosis of autoimmune PAP. Patients with a known condition or exposure associated with secondary PAP who do not have increased GM-CSF autoantibodies are diagnosed accordingly. Otherwise, patients should be screened for serum GM-CSF levels and GM-CSF function signaling by flow cytometry, as well as genomic analysis for mutations affecting GM-CSF receptor genes (CSF2RA and CSF2RB) and those related to surfactant production (SFTPA, SFTPB, SFTPC), to confirm a diagnosis of hereditary, congenital, or unclassified PAP, all of which are exceedingly rare. (Adapted from “Pulmonary alveolar proteinosis,” by BC Trapnell, 2019, Nat Rev Dis Primers, 5:16:8.).