BBB disruption and pleocytosis

After bacteria have accomplished invasion into the CNS, they multiply and induce the release of a multitude of proinflammatory and toxic compounds, leading to the hallmarks of bacterial meningitis, the disintegration of blood-CNS barriers and the infiltration of leukocytes with subsequent pleocytosis.

Animal experiments failed to demonstrate a close association between blood-CNS barrier breakdown and CSF pleocytosis [148-150], and clinical observations have shown that either pleocytosis without significant CNS barrier dysfunction [151, 152], apurulent courses of bacterial meningitis [153] or blood-CNS barrier dysfunction in neutropenic patients [154] do occur. This has led to the conclusion that initial bacterial entry into the CNS per se takes place without pleocytosis and blood-CNS barrier breakdown, and that bacteria can then induce inflammation or other alterations such as pleocytosis or increased BBB permeability [1]. Although not in the focus of this review, it is of note that cerebral edema, increased intracranial pressure and altered cerebral blood flow occur in bacterial meningitis, resulting in neuronal injury.

Leukocyte recruitment

CSF pleocytosis is a result of leukocyte extravasation from the circulation into the extravascular space after chemotactic attraction [155, 156]. It occurs through a tightly controlled multistep process governed by the sequential activation of adhesion receptors and their ligands on both leukocytes and the endothelium [157, 158]. The multistep paradigm postulates that four sequential steps (capture, activation, adhesion strengthening, transmigration) are involved in this cascade.

The initial capture, the 'tethering' of leukocytes as well as subsequent rolling are mediated by adhesion molecules such as P-, E-, and L-selectin, and their corresponding carbohydrate ligands. Firm adhesion of leukocytes to the endothelium is subsequently mediated by a family of integrins, which have to be 'activated' by a proinflammatory cytokine (e.g., IL-1|3), chemokines (e.g., IL-8), complement products, or bacterial cell wall components to reach adequate avidity [159]. Macrophage antigen 1 (MAC-1; CD11b/CD18) from the Ig superfamily of adhesion receptors is the predominant integrin involved in neutrophil binding to their endothelial ligands. Intercellular adhesion molecule (ICAM)-1 exhibits low constitutive levels on the cell surface of the resting endothelium but is markedly induced by exposure to inflammatory stimuli and is the most important endothelial ligand for MAC-1.

In experiments with HBMEC, challenge with S. agalactiae led to the up-regulation of a number of CXC chemokines for recruitment of neutrophils, GM-CSF for bone marrow stimulation of neutrophils, ICAM-1 for adhesion of neutrophils, and Mcl-1 for prevention of neutrophil apoptosis, demonstrating the interconnection between microbial infection and leukocyte activation [91]. Infection of HBMEC with L. monocytogenes led to a significant expression of ICAM-1 [160] as well as HBMEC challenge with Plasmodium falciparum-infected erythrocytes [161].

Antibodies directed against the adhesion molecules MAC-1 or ICAM-1 profoundly attenuated invasion of neutrophils during experimental meningitis and led to significant reductions in intracranial complications such as brain edema formation [162].

An animal model of experimental autoimmune encephalomyelitis (EAE) demonstrates the involvement of the CP in leukocyte recruitment. Using immunohistochemistry and in situ hybridization, expression of VCAM-1, ICAM-1 and MAdCAM-1 has been observed on the CP epithelial cells in combination with a complete absence of these structures on the fenestrated endothelium [163].

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