title: Nocardia-induced granulocyte macrophage colony-stimulating factor is neutralized by autoantibodies in disseminated/extrapulmonary nocardiosis.
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.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Rosen
authors.affiliation: Nephrology and Infectious Diseases Research and Development Group, INEB (I3S), University of Porto Department of Infectious Diseases, São João Hospital Center, Porto, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Rocha Pereira
authors.affiliation: Department of Infectious Diseases, São João Hospital Center, Porto, Portugal.
authors.forename: Cristóvão
authors.initials: C
authors.lastname: Figueiredo
authors.affiliation: Walter Reed National Military Medical Center.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Fiske
authors.affiliation: Walter Reed National Military Medical Center Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Roseanne A
authors.initials: RA
authors.lastname: Ressner
authors.affiliation: Department of Allergy/Immunology, Permanente Medical Group, Kaiser Permanente Northwest, Clackamas, Oregon.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Hong
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Gregg
authors.affiliation: Department of Internal Medicine.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Henry
authors.affiliation: Department of Internal Medicine.
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Pak
authors.affiliation: Department of Infectious Disease.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Baumgarten
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Seoane
authors.affiliation: Department of Infectious Disease.
authors.forename: Julia
authors.initials: J
authors.lastname: Garcia-Diaz
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.affiliation: Department of Microbiology Service, Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Zelazny
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Browne
mesh_terms: D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood*; D001323:Autoantibodies / Q000097:blood*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009615:Nocardia / Q000276:immunology*; D009617:Nocardia Infections / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: GM-CSF; adult-onset immunodeficiency; anticytokine autoantibodies; nocardiosis; opportunistic infection