Neutralizing GM-CSF autoantibodies impair neutrophil antifungal effector function in a patient with aspergillosis Journal Article


Authors: Wishart, A. L.; Pechacek, J.; Rosen, L. B.; Desai, J. V.; Zarakas, M. A.; Webb, T.; Pittaluga, S.; Seyedmousavi, A.; Hohl, T. M.; Kuhns, D. B.; Holland, S. M.; Lionakis, M. S.
Article Title: Neutralizing GM-CSF autoantibodies impair neutrophil antifungal effector function in a patient with aspergillosis
Abstract: Objectives: To present a putatively immunocompetent patient with locally invasive aspergillosis and neutralizing autoantibodies (Aabs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) and to characterize GM-CSF Aab-mediated impairments in neutrophil anti-Aspergillus effector function. Methods: Imaging studies and histological analyses of infected tissue were employed to diagnose sino-orbital aspergillosis and monitor antifungal treatment responses. Whole genome sequencing (WGS), dihydrorhodamine testing, and particle-based Aab detection were employed to assess for the underlying etiology of fungal disease. Neutrophils from the patient and healthy donors were harvested from peripheral blood and underwent evaluations for cell viability, fungal conidial uptake and intracellular killing, conidial germination inhibition, hyphal damage, reactive oxygen species (ROS) production, and GM-CSF-induced STAT5 phosphorylation. Results: We describe a 61-year-old woman who developed isavuconazole-refractory sino-orbital aspergillosis with a lymphoplasmacytic infiltrate in the infected tissue without neutrophil infiltration. WGS revealed no known inborn error of immunity to account for infection susceptibility. The patient carried high titers of neutralizing Aabs against GM-CSF without associated pulmonary alveolar proteinosis (PAP) or other opportunistic infections. Although the patient's neutrophils exhibited no intrinsic antifungal effector function defects, the patient's GM-CSF Aab-containing serum inhibited GM-CSF-mediated neutrophil activation and Aspergillus-induced ROS production. The infection remitted with long-term posaconazole administration. Conclusions: Invasive aspergillosis may occur in patients with neutralizing GM-CSF Aabs, even in the absence of PAP or other opportunistic infections. GM-CSF Aabs impair GM-CSF-mediated neutrophil activation and Aspergillus-induced ROS production, which may contribute to the invasive fungal infection susceptibility. GM-CSF Aabs should be tested in putatively immunocompetent individuals who develop invasive mold disease. © 2025 Elsevier B.V., All rights reserved.
Keywords: reactive oxygen species; neutrophils; autoantibodies; invasive aspergillosis; granulocyte macrophage-colony stimulating factor
Journal Title: Journal of Infection
Volume: 91
Issue: 3
ISSN: 0163-4453
Publisher: W.B. Saunders Co.  
Publication status: Online ahead of print
Date Published: 2025-08-11
Start Page: 106588
Language: English
DOI: 10.1016/j.jinf.2025.106588
PUBMED: 40812454
PROVIDER: scopus
PMCID: PMC12404695
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Tobias Martin Hohl
    106 Hohl