Page 53 - Human Lyme Neuroborreliosis

The Blood-brain Barrier 37

Human cocultured human endothelial cells and astrocytes increase the
expression of ICAM-1 due to inflammatory activation by hypoxia in vitro
[69]. Other studies have demonstrated that astrocytes are a source of IL-6,
TNF-?, and MCP-1 which contribute to the CNS inflammatory response [70].
Trafficking of PBMC along the endothelial cell of the BBB is a complex
mechanism that involves major subsets of immune cells and relies heavily on
astrocyte, microglia and endothelial cell interactions, moreover, astrocytes
appear to be an active factor in the recruitment of immune cells, while
microglia appear to curtail this activity.

Implications for Lyme Neuroborreliosis

Interest in concepts of BBB disruption in Lyme neuroborreliosis (LNB)
commenced with a decade of experimental and clinical observations in early
1990 focusing on the etiopathogenesis of CNS manifestations, notably
encephalopathy in acute and chronic Lyme infection. The mechanisms by
which bacteria breached the BBB had been incompletely understood however
it had been proposed that during pneumococcal bacteremia, microbial factors
acted directly or indirectly to trigger production of endogenous inflammatory
mediators that altered endothelial TJ to facilitate bacterial entry.

In 1990, Szcezepanski and colleagues [71] studied the emigration of B.
burgdorferi, the spirochetal agent of Lyme disease, across cultured human
umbilical vein EC (HUVEC). Low passage human clinical isolates (HSA1 and
HBD1) cultured from skin and blood respectively of patients with erythema
migrains (EM), and a tick isolate (T11) from I.dammini collected in Montauk,
NY, adhered 22 to 30-fold greater than the continuously passaged strain B31
to the subendothelial matrix. Spirochete binding and adherence to the
subendothelial matrix was inhibited 48 to 63% by pretreatment of the matrix
with anti-serum to fibronectin, a major component of the matrix produced by
cultured EC and a constituent of the basement membrane of blood vessels in
vivo. The inhibition of spirochete adherence to the matrix by anti-fibronectin
indicated that the spirochetes recognized the insoluble matrix form of this
glycoprotein. Spirochete migration across endothelial monolayers cultured on
amniotic membrane was increased when the monolayers were damaged by
chemical or physical means. Electron microscopic examination of spirochete-
endothelial interactions demonstrated the presence of spirochetes in the
intercellular junctions between EC as well as beneath the monolayers.

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