title: Intrathecal production and secretion of vascular endothelial growth factor during Cryptococcal Meningitis.
abstract: BACKGROUND
  Patients with cryptococcal meningitis (CM) show elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption in most cases. Elevated ICP is an important contributor to mortality. Vascular endothelial growth factor (VEGF) might be the mediator of BBB disruption during CM.
  
  
  METHODS
  We measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) of 95 patients and 63 control subjects, and we analyzed the required trigger and cellular source of VEGF secretion in vitro.
  
  
  RESULTS
  Cryptococcus neoformans and its capsular antigens dose-dependently induced VEGF secretion by polymorphonuclear neutrophils, monocytes, and peripheral blood mononuclear cells (PBMCs). VEGF production by PBMCs induced by antigens strongly exceeded production by monocytes (P<.001). The addition of major histocompatibility complex class II antibody inhibited this production of VEGF (P=.005). Confirming the in vitro data, patients with CM showed significantly elevated VEGF levels in CSF (P<.001), plasma (P=.028), and serum (P<.001), compared with healthy control subjects. Calculated VEGF indices demonstrated that VEGF was produced intrathecally.
  
  
  CONCLUSIONS
  Our findings suggest that VEGF plays a role in the pathophysiology of CM. We propose that CD4(+) T lymphocytes--stimulated by monocytes acting as antigen-presenting cells--are the cells that produce VEGF in response to cryptococcal antigens.
authors.affiliation: Department of Acute Medicine and Infectious Diseases and Eijkman-Winkler Institute for Microbiology, University Medical Center Utrecht, The Netherlands. f.e.j.coenjaerts@lab.azu.nl.
authors.forename: Frank E J
authors.initials: FE
authors.lastname: Coenjaerts
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Flier
authors.forename: Pauline N M
authors.initials: PN
authors.lastname: Mwinzi
authors.forename: Annemarie E
authors.initials: AE
authors.lastname: Brouwer
authors.forename: Jelle
authors.initials: J
authors.lastname: Scharringa
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Chaka
authors.forename: Marieke
authors.initials: M
authors.lastname: Aarts
authors.forename: Adul
authors.initials: A
authors.lastname: Rajanuwong
authors.forename: David A
authors.initials: DA
authors.lastname: van de Vijver
authors.forename: Tom S
authors.initials: TS
authors.lastname: Harrison
authors.forename: Andy I M
authors.initials: AI
authors.lastname: Hoepelman
mesh_terms: D000328:Adult; D017951:Antigen Presentation; D000946:Antigens, Fungal / Q000276:immunology; D001812:Blood-Brain Barrier; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid* / Q000276:immunology; D008875:Middle Aged; D042461:Vascular Endothelial Growth Factor A / Q000134:cerebrospinal fluid* / Q000502:physiology
chemical_list: D000946:Antigens, Fungal; D042461:Vascular Endothelial Growth Factor A