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

2021 ◽  
Vol 12 ◽  
Author(s):  
Ali Ataya ◽  
Vijaya Knight ◽  
Brenna C. Carey ◽  
Elinor Lee ◽  
Elizabeth J. Tarling ◽  
...  
Keyword(s):  
Opportunistic Infections ◽  
Pulmonary Alveolar Proteinosis ◽  
Cell Types ◽  
Pulmonary Insufficiency ◽  
Gm Csf ◽  
Host Immune Responses ◽  
Susceptibility To Infection ◽  
Alveolar Proteinosis ◽  
Macrophage Colony

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.

scholarly journals The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.

1996 ◽  
Vol 183 (6) ◽  
pp. 2657-2662 ◽  
Author(s):  
R Nishinakamura ◽  
R Wiler ◽  
U Dirksen ◽  
Y Morikawa ◽  
K Arai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Pulmonary Alveolar Proteinosis ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Stimulating Factor

Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation.

scholarly journals Therapeutic effect of subcutaneous injection of low dose recombinant human granulocyte-macrophage colony-stimulating factor on pulmonary alveolar proteinosis

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fen Zhang ◽  
Dong Weng ◽  
Yiliang Su ◽  
Chengsheng Yin ◽  
Li Shen ◽  
...  
Keyword(s):  
Subcutaneous Injection ◽  
Low Dose ◽  
Pulmonary Alveolar Proteinosis ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Objective To observe the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for pulmonary alveolar proteinosis (PAP). Materials and methods A total of 55 patients with PAP were screened at Shanghai Pulmonary Hospital between May 2014 and May 2018. Among these, 42 were diagnosed with idiopathic PAP, 24 were included in this study, 20 were treated for 6 months, and 17 were followed up for additional 6 months. All patients received a subcutaneous injection of 75μg/d GM-CSF qd for 1 month. The therapeutic dose was adjusted according to the changes in the lesions of chest CT. If the lesions were absorbed, subcutaneous injections of 75μg/d GM- CSF qd and 75μg/d GM-CSF qod were given for 2 and 3 months, otherwise, the dose was increased to 150μg/d GM-CSF qd and 150μg/d qod for 2 and 3 months, respectively. All cases were treated once a day in the first 3 months and once every other day in the last 3 months. The total course of treatment was 6 months. After withdrawal, the patients were followed up for another 6 months. The deadline of follow up was September 30, 2019. Results Twenty patients completed the treatment and efficacy evaluation. One patient was completely cured, 16 cases improved, three cases were noneffective. After 1-month evaluation, 12 patients received an increased dose (150μg) from the second month of treatment. Seventeen patients completed the 12-month follow-up, among which fourteen improved. CT showed the lesions were slightly increased in three cases. Economic burden was the following: RMB 7324–15,190 Yuan were required for the 6-month treatment course, which is significantly lower compared to other treatment methods. Conclusion Subcutaneous injection of rhGM-CSF at low dose (75μg-150μg /d) is effective treatment for patients with idiopathic PAP. Trial registration NCT01983657. Registered 16 April 2013.

Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications

2012 ◽  
Vol 447 (2) ◽  
pp. 205-215 ◽  
Author(s):  
Michaela Blech ◽  
Daniel Seeliger ◽  
Barbara Kistler ◽  
Margit M. T. Bauer ◽  
Mathias Hafner ◽  
...  
Keyword(s):  
Pulmonary Alveolar Proteinosis ◽  
Complex Structure ◽  
Structural Basis ◽  
Gm Csf ◽  
Reliable Model ◽  
Perturbation Data ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Stimulating Factor

Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen–autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF–GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.

scholarly journals Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRα gene in the X chromosome pseudoautosomal region 1

2008 ◽  
Vol 205 (12) ◽  
pp. 2711-2716 ◽  
Author(s):  
Margarita Martinez-Moczygemba ◽  
Minh L. Doan ◽  
Okan Elidemir ◽  
Leland L. Fan ◽  
Sau Wai Cheung ◽  
...  
Keyword(s):  
X Chromosome ◽  
Pulmonary Alveolar Proteinosis ◽  
Pseudoautosomal Region ◽  
Severe Respiratory Distress ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Alveolar Proteinosis ◽  
Macrophage Colony ◽  
Underlying Diseases ◽  
Β Chain

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. The importance of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of PAP has been confirmed in humans and mice, wherein GM-CSF signaling is required for pulmonary alveolar macrophage catabolism of surfactant. PAP is caused by disruption of GM-CSF signaling in these cells, and is usually caused by neutralizing autoantibodies to GM-CSF or is secondary to other underlying diseases. Rarely, genetic defects in surfactant proteins or the common β chain for the GM-CSF receptor (GM-CSFR) are causal. Using a combination of cellular, molecular, and genomic approaches, we provide the first evidence that PAP can result from a genetic deficiency of the GM-CSFR α chain, encoded in the X-chromosome pseudoautosomal region 1.

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