Lindsey B Rosen1, Nuno Rocha Pereira2, Cristóvão Figueiredo3, Lauren C Fiske4, Roseanne A Ressner5, Julie C Hong6, Kevin S Gregg7, Tracey L Henry8, Kirk J Pak8, Katherine L Baumgarten9, Leonardo Seoane10, Julia Garcia-Diaz9, Kenneth N Olivier1, Adrian M Zelazny11, Steven M Holland1, Sarah K Browne1. 1. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. 2. Nephrology and Infectious Diseases Research and Development Group, INEB (I3S), University of Porto Department of Infectious Diseases, São João Hospital Center, Porto, Portugal. 3. Department of Infectious Diseases, São João Hospital Center, Porto, Portugal. 4. Walter Reed National Military Medical Center. 5. Walter Reed National Military Medical Center Uniformed Services University of the Health Sciences, Bethesda, Maryland. 6. Department of Allergy/Immunology, Permanente Medical Group, Kaiser Permanente Northwest, Clackamas, Oregon. 7. Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor. 8. Department of Internal Medicine. 9. Department of Infectious Disease. 10. Department of Pulmonary and Critical Care Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana. 11. Department of Microbiology Service, Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland.
Abstract
BACKGROUND: Nocardia species cause infections in both immunocompromised and otherwise immunocompetent patients, although the mechanisms defining susceptibility in the latter group are elusive. Anticytokine autoantibodies are an emerging cause of pathogen-specific susceptibility in previously healthy human immunodeficiency virus-uninfected adults, including anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies with cryptococcal meningitis. METHODS: Plasma from patients with disseminated/extrapulmonary nocardiosis and healthy controls was screened for anticytokine autoantibodies using a particle-based approach. Autoantibody function was assessed by intranuclear staining for GM-CSF-induced STAT5 phosphorylation in normal cells incubated with either patient or normal plasma. GM-CSF-mediated cellular activation by Nocardia was assessed by staining for intracellular cytokine production and intranuclear STAT5 phosphorylation. RESULTS: We identified neutralizing anti-GM-CSF autoantibodies in 5 of 7 patients studied with central nervous system nocardiosis and in no healthy controls (n = 14). GM-CSF production was induced by Nocardia in vitro, suggesting a causative role for anti-GM-CSF autoantibodies in Nocardia susceptibility and dissemination. CONCLUSIONS: In previously healthy adults with otherwise unexplained disseminated/extrapulmonary Nocardia infections, anti-GM-CSF autoantibodies should be considered. Their presence may suggest that these patients may be at risk for later development of pulmonary alveolar proteinosis or other opportunistic infections, and that patients may benefit from therapeutic GM-CSF administration. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
BACKGROUND:Nocardia species cause infections in both immunocompromised and otherwise immunocompetent patients, although the mechanisms defining susceptibility in the latter group are elusive. Anticytokine autoantibodies are an emerging cause of pathogen-specific susceptibility in previously healthy human immunodeficiency virus-uninfected adults, including anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies with cryptococcal meningitis. METHODS: Plasma from patients with disseminated/extrapulmonary nocardiosis and healthy controls was screened for anticytokine autoantibodies using a particle-based approach. Autoantibody function was assessed by intranuclear staining for GM-CSF-induced STAT5 phosphorylation in normal cells incubated with either patient or normal plasma. GM-CSF-mediated cellular activation by Nocardia was assessed by staining for intracellular cytokine production and intranuclear STAT5 phosphorylation. RESULTS: We identified neutralizing anti-GM-CSF autoantibodies in 5 of 7 patients studied with central nervous system nocardiosis and in no healthy controls (n = 14). GM-CSF production was induced by Nocardia in vitro, suggesting a causative role for anti-GM-CSF autoantibodies in Nocardia susceptibility and dissemination. CONCLUSIONS: In previously healthy adults with otherwise unexplained disseminated/extrapulmonary Nocardia infections, anti-GM-CSF autoantibodies should be considered. Their presence may suggest that these patients may be at risk for later development of pulmonary alveolar proteinosis or other opportunistic infections, and that patients may benefit from therapeutic GM-CSF administration. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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