“Regulation Of Pulmonary Macrophage Function In Health And Disease” – A Synopsis

Below is a video and synopsis of the talk “Regulation Of Pulmonary Macrophage Function In Health And Disease” by Dr. Bruce Trapnell at the Vera Moulton Wall Center for Pulmonary Vascular Disease:

Summary

• GM-CSF is important for macrophages to clear adenovirus transfections
• Normally, an adenovirus exits the endosome and is targets the nucleus of the cell and dumps its DNA into the nucleus
• In cells, GM-CSF redirects adenovirus to lysosomes via PU.1
• GM-CSF receptor has pleiotropic effects on macrophages: low concentrations of GM-CSF leads to signaling that induces differentiation and survival of macrophages, and at higher concentrations, that pathway is shut down and another pathway occurs through the receptor that leads to growth and priming functions as well as survival.
• Amount of GM-CSF is also important: too little GM-CSF results in inability of macrophages to clear pulmonary surfactant, so lung fills with surfactant, and too much GM-CSF results in accumulation of macrophages in lung (to the point where it looks like desquamative interstitial pneumonia)
• GM-CSF autoantibodies are present in idiopathic pulmonary alveolar proteinosis (PAP) patients, but also in healthy controls, albeit at lower levels. Autoantibody levels don’t correlate with disease severity, making the presence of GM-CSF autoantibodies as a cause or epiphenomenon of disease hard to determine.
• Koch’s Postulate approach was used to determine if GM-CSF plays a causative role in PAP:
  1. Showed elevated levels of antibody
  2. Purification of GM-CSF autoantibody achieved 
  3. Reproduced key pathologic features in healthy primates by injecting them with antibodies
  4. Antibodies were isolated from monkeys and patients and placed in whole blood incubated with GM-CSF, and it was found that GM-CSF signaling was decreased.
• Due to above postulates being satisfied, GM-CSF autoantibodies are thus found to be cause of PAP.
• There is a critical threshold, about 5ug/mL, where the level of auto-antibody to GM-CSF can cause PAP.
• GM-CSF affects other immune cells, such as neutrophils, and it was found that neutrophil phagocytosis is reduced in PAP due to GM-CSF autoantibody.
• CSF2RA or CSF2RB (which are GM-CSF receptor genes) mutations give rise to clinical phenotype of PAP, due to inability of GM-CSF to bind to receptor. In patients with these mutations, you will have elevated serum levels of GM-CSF.
• GM-CSF is necessary for the maturation of alveolar macrophage precursors in the lung to mature cells that are involved in surfactant catabolism, as well as host defense.
• Neutrophils develop from precursors to mature cells via absence of GM-CSF, but GM-CSF is needed for the proper functioning of neutrophils in host defense.
• Classification of PAP diseases by Mechanism:
  • Disruption of GM-CSF signaling:
    1. Autoimmune PAP (anti-GM-CSF antibodies)
    2. GM-CSF receptor dysfunction (CSF2RA/B mutation)
  • Disruption of macrophage functions/numbers:
    1. Hematologic disorders (myelodysplasia, leukemia, etc.)
    2. Immune deficiency
    3. Chronic infection (HIV)
    4. Toxic dust inhalation (silica, etc.)
    5. Genetic disorders (GATA2, SLC7A7)
  • Disruption of surfactant structure/function (genetic):
    1. Surfactant protein deficiency/dysfunction (SFTPB, SFTPC)
    2. Surfactant lipid disruption (ABCA3)
  • Lung development/surfactant production (NKX2.1)
• Therapy for PAP is Saline Whole Lung Lavage – and there is a need for other therapies
• Inhalation of rhGM-CSF (recombinant human GM-CSF) improves oxygen delivery in ~65-90% of PAP patients
• Pulmonary Macrophage Transplantation Therapy is being considered for hereditary PAP.
• GM-CSF regulates alveolar macrophage population size via a reciprocal feedback mechanism: mature macrophage cells consume GM-CSF and mature and proliferate in response to it and divide, and in absence of GM-CSF (due to situations with high GM-CSF antibodies for example), M-CSF is expressed at high levels and keeps these cells alive, but it doesn’t allow them to function very well.