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bacterial infections, or those that occur during inflammatory diseases, such as multiple
sclerosis and stroke, are characterized by immune-cell entry across the blood-CNS
barriers. In the animal model of experimental autoimmune encephalomyelitis, which
is considered the prototype model for the human disease multiple sclerosis, T cells are
found to penetrate the CNS and initiate the molecular and cellular events leading to
edema, inflammation, and demyelination in the CNS [10] . Here, in addition to the BBB
as the entry point for the circulating immune cells into the CNS, the CP blood-CSF
barrier is established as an equally critical brain passage for circulating lymphocytes.
During experimental autoimmune encephalitis (EAE), the CP undergoes deleteri-
ous ultrastructural changes, including up-regulated expression of VCAM-1, ICAM-1,
and MAdCAM-1 localized on the apical surface of CP epithelial cells, but completely
lacking on the fenestrated endothelial cells. The increased ICAM-1, VCAM-1, and
MAdCAM-1 expression in CP epithelium mediates binding of lymphocytes via their
known ligands. Parallel in vitro studies revealed that CP epithelial cells can be induced
to express ICAM-1, VCAM-1, MAdCAM-1, and, additionally, MHC class I and II
molecules on their surfaces [10] , further advancing the notion that CP is closely asso-
ciated with CNS immunosurveillance. Taken together, investigations into the mecha-
nisms underlying immune-cell entry into the CNS, especially the sustained integrity of
the CP blood-CSF barrier during pathological conditions, may reveal potential treat-
ments that can be directed against CNS immune or inflammatory diseases.
4.4 Choroid Plexus and Brain Development
As noted in Section 4.3, the strategic location of the CP makes it an excellent brain
structure for distributing molecules to the brain. In studies following this logic, CP has
been demonstrated to be a major source of biologically active compounds ( Table 4.1 ).
These capabilities allow the CP to monitor and respond to the biochemistry of the
brain by manipulating and maintaining baseline levels of the extracellular milieu
throughout the CNS. The molecules secreted by the CP gain access to the brain
parenchyma via volume transmission, convective distribution, and intraparenchymal
diffusion/receptor-mediated retrograde transport [1-5,11] .
During development, CPs form early during embryogenesis, assisting in control
of the developing extracellular environment [12] by secreting morphogens, mitogens,
and trophic factors that guide and pattern both the general and specific growth of
the brain [9,13] . In particular, the embryonic CP contains high levels of insulin-like
growth factor (IGF)-II localized in the floor plate of the hindbrain, which prompted
speculations that CP-derived IGF-II diffuses to and binds to IGF receptors on the
floor plate cells and activates their role in guiding spinal axon growth [14] . Further
support for CP contribution to morphogenesis comes from demonstrations that the
radial migration of cerebral cortical neurons from the ventricular and subventricu-
lar zone to the cortical plate is governed by gradients of soluble factors, such as
CP-secreted Slit proteins [15-17] . In vitro , CP is found to secrete a soluble factor,
related to Slit2, that diffuses through the CSF and aids in establishing a gradient
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