Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang, Yanni; Thomson, Christy A.; Allan, Lenka L.; Jackson, Leland J.; Olson, Melanie; Hercus, Timothy R.; Nero, Tracy L.; Turner, Amanda; Parker, Michael W.; López, AF; Waddell, Thomas K.; Anderson, Gary P.; Hamilton, John A.; Schrader, John W.

doi:10.1073/pnas.1216011110

Cited by 39 publications

(31 citation statements)

References 58 publications

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“…Secondary PAP develops in association with functional impairment or reduced number of alveolar macrophages such as due to some hematologic cancers, inhalation of inorganic dusts or toxic fumes and pharmacologic immunosuppression [51]. While idiopathic PAP was eventually identified as an autoimmune disease caused by GM-CSF autoantibodies [51–53], the primary stimulus leading to the production of GM-CSF autoantibodies remains unknown [54,55]. To advance the understanding of PAP pathogenesis, exogenous GM-CSF was administered to patients with acquired PAP, which appeared to benefit patients with therapeutic efficacy [56,57].…”

Section: Gm-csf Neutralizing Antibody and Susceptibility To Cryptomentioning

confidence: 99%

Is Cryptococcus gattii a Primary Pathogen?

Kwon‐Chung

Saijo

2015

JoF

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The two etiologic agents of cryptococcal meningoencephalitis, Cryptococcus neoformans and C. gattii, have been commonly designated as either an opportunistic pathogen for the first species or as a primary pathogen for the second species. Such a distinction has been based on epidemiological findings that the majority of patients presenting meningoencephalitis caused by C. neoformans are immunocompromised while C. gattii infection has been reported more often in immunocompetent patients. A recent report, however, showed that GM-CSF (granulocyte-macrophage colony-stimulating factor) neutralizing antibodies were prevalent in the plasma of “apparently immunocompetent” C. gattii patients with meningoencephalitis. Because GM-CSF is essential for differentiation of monocytes to macrophages and modulating the immune response, it is not surprising that the lack of GM-CSF function predisposes otherwise healthy individuals to infection via inhalation of environmental pathogens such as C. gattii. Since the test for anti-GM-CSF autoantibodies is not included in routine immunological profiling at most hospitals, healthy patients with GM-CSF neutralizing antibodies are usually categorized as immunocompetent. It is likely that a comprehensive immunological evaluation of patients with C. gattii meningoencephalitis, who had been diagnosed as immunocompetent, would reveal a majority of them had hidden immune dysfunction. This paper reviews the relationship between GM-CSF neutralizing antibodies and the risk for C. gattii infection with CNS involvement.

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Section: Gm-csf Neutralizing Antibody and Susceptibility To Cryptomentioning

confidence: 99%

Is Cryptococcus gattii a Primary Pathogen?

Kwon‐Chung

Saijo

2015

JoF

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“…Formal testing of this hypothesis may be significant for human disease as well. To-date, no studies have examined the importance of Tfh cells, CD275-CD278 interactions, and/or IL-21 in human disease, though GM-CSF-specific autoantibodies from aPAP patients are heavily somatically hypermutated 16 suggesting a role for Tfh cells.…”

Section: Discussionmentioning

confidence: 99%

“…aPAP patients treated with rituximab, a B cell depleting anti-CD20 monoclonal antibody, exhibit improvement in lipid homeostasis and overall outcome, illustrating that B cells and antibody are necessary for the pathology 13-15 . GM-CSF-specific autoantibodies in aPAP patients are polyclonal and somatically hypermutated IgG antibodies 16, 17 . Interestingly, GM-CSF-specific IgG autoantibodies are also detectable in healthy individuals, though titers are significantly lower compared to aPAP patients 18 .…”

Section: Introductionmentioning

confidence: 99%

Autoantibody-Mediated Pulmonary Alveolar Proteinosis in Rasgrp1-Deficient Mice

Ferretti

Fortwendel

Gebb

et al. 2016

The Journal of Immunology

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Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome caused by the accumulation of surfactants in the alveoli. The most prevalent clinical form of PAP is autoimmune (aPAP) whereby IgG autoantibodies neutralize granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a pleiotropic cytokine that promotes the differentiation, survival, and activation of alveolar macrophages, the cells responsible for surfactant degradation. IgG-mediated neutralization of GM-CSF thereby inhibits alveolar macrophage homeostasis and function, leading to surfactant accumulation and innate immunodeficiency. Importantly, there are no rodent models for this disease, and therefore underlying immune mechanisms regulating GM-CSF-specific IgG in aPAP are not well understood. Herein, we identify that autoimmune-prone Rasgrp1-deficient mice develop aPAP: 1) Rasgrp1-deficient mice exhibit reduced pulmonary compliance as well as lung histopathology characteristic of PAP; 2) alveolar macrophages from Rasgrp1-deficient mice are enlarged and exhibit reduced surfactant degradation; 3) the concentration of GM-CSF-specific IgG is elevated in both serum and bronchial-alveolar lavage fluid (BALF) from Rasgrp1-deficient mice; 4) GM-CSF-specific IgG is capable of neutralizing GM-CSF bioactivity; and 5) Rasgrp1-deficient mice also lacking CD275/ICOSL, a molecule necessary for conventional T cell-dependent antibody production, have reduced GM-CSF-specific autoantibody and do not develop PAP. Collectively these studies reveal that Rasgrp1-deficient mice represent the first rodent model for aPAP.

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“…It is supposed to account for more than 90% of all human PAP diseases. A series of GM-CSF neutralizing autoantibodies have been recently characterized (Wang et al 2013). Particle exposure is generally not considered to be a cause.…”

Section: Introductionmentioning

confidence: 99%

Particle-induced Pulmonary Alveolar Proteinosis and Subsequent Inflammation and Fibrosis: A Toxicologic and Pathologic Review

Bomhard¹

2017

Toxicol Pathol

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This review analyzes the published data on cases of pulmonary alveolar proteinosis (PAP) in workers inhaling crystalline aluminum, indium, silicon, and titanium particles and possible sequelae, that is, inflammation and fibrosis, and compares these findings with those from animal experiments. In inhalation studies in rodents using crystalline indium and gallium compounds, pronounced PAP followed by inflammation and fibrosis down to very low concentration ranges have been reported. Crystalline aluminum, silicon, and titanium compounds also induced comparable pulmonary changes in animals, though at higher exposure levels. Laboratory animal species appear to react to the induction of PAP with varying degrees of sensitivity. The sensitivity of humans to environmental causes of PAP seems to be relatively low. Up to now, no cases of PAP, or other pulmonary diseases in humans, have been described for gallium compounds. However, a hazard potential can be assumed based on the results of animal studies. Specific particle properties, responsible for the induction of PAP and its sequelae, have not been identified. This review provides indications that, both in animal studies and in humans, PAP is not often recognized due to the absence of properly directed investigation or is concealed behind other forms of lung pathology.

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Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Cited by 39 publications

References 58 publications

Is Cryptococcus gattii a Primary Pathogen?

Is Cryptococcus gattii a Primary Pathogen?

Autoantibody-Mediated Pulmonary Alveolar Proteinosis in Rasgrp1-Deficient Mice

Particle-induced Pulmonary Alveolar Proteinosis and Subsequent Inflammation and Fibrosis: A Toxicologic and Pathologic Review

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