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.
Bibliographical noteFunding Information:
Financial support: Medical Branch of the Dutch Sciences Organization (NWO-MW AGIKO 920-03-077 to M.v.d.F.); Utrecht Scholarship Program, UtrechtUniversity (fellowship to P.N.M.M.); Lancet International Fellowship (RH/H9-140202 to A.E.B.); Wellcome Trust Advanced Training Fellowship (GRO52199 to T.S.H.).