Leukocyte Trafficking Within The Central Nervous System

Traditional immunological surveillance of the brain is restricted by the blood brain barrier, a customized vessel endothelium compacted by functional complexes that effectively eliminate any space between adjacent endothelial cells [162], This barrier blocks the diffusion of blood-borne substances as well as immigration of circulating cells into the brain parenchyma. Typically, T, B and natural killer cells do not enter into neural tissue under homeostatic conditions [163], However, violation of this barrier is a primary factor in several serious diseases of the central nervous system (CNS), such as multiple sclerosis and infection-induced encephalitis [163], Ironically, in several CNS infections, the offending organism utilizes leukocytes as the vehicle for brain entry [164],

Several studies into the mechanisms of EAE have observed that only activated T cells adoptively transferred into rats could traffic to the neural parenchyma [165,166]. B cells are similarly implicated with several neuroinflammatory diseases exhibiting high levels of IgG antibody within the cerebrospinal fluid (CSF), which normally has IgG levels 1000 fold less than those observed in serum. The observation of "oligoclonal bands" of IgG - discrete bands detected by electrophoresis - within the CSF led to the hypothesis that activated B cells enter the CNS under activated conditions and even establish plasma cells inside the blood brain barrier [2], Upon administration of antigen beyond an intact blood brain barrier via cannulization, in combination with peripheral immunization, Harling-Berg et al. [167] observed that antigen specific B cells could be detected within the rat brain. The general consensus is that B cells need a prerequisite activation signal similar to T cells before traversing the endothelial lining to the interior of the CNS. However, some resistance to this hypothesis exists based on the observation of some T and B lymphocytes within the CNS under steady-state conditions [164].

T cells found within the CSF have higher expression of CXCR3 than those in the periphery, and a neutralizing antibody against its ligand CXCL10/IP10 is capable of protection against EAE, however mice with a targeted deletion in CXCL10/IP10 are equally susceptible compared to wild-type mice [168-170]. Similarly, CCL3/MIP-la or CCR5 knockout mice are not protected from EAE, despite data showing the protective effect of anti-CCL3/MIP-1 a antibody [169,171], y8 T cells exhibiting an activated phenotype can be demonstrated in the CNS during EAE, however the mechanism of trafficking has not been characterized [172], In a murine model of neurocysticercosis, y8 T cells were the predominant subset recruited to the CNS, and animals depleted of y8 lymphocytes had decreased severity of disease [173,174], Increased expression of CCL2/MCP-1, CCL3/MIP-la, CCL5/RANTES, CXCL2/MIP-2 and CCL11/eotaxin is correlated with disease onset [175], TCR8' mice induced with neurocysticercosis demonstrated reduced expression of these chemokines and decreases in recruitment of NK, B, a[3 T and dendritic cells to the brain [175].

Unlike lymphocytes, macrophage/monocyte lineage cells are present within the CNS during resting conditions [163], The types of macrophages that can be found within the CNS are expansive with several phenotypically distinct subsets occupying different regions of the brain. Some of these cell types, such as parenchymal microglial cells, appear early during fetal life with little or no replenishment from the bone marrow required. Other cell types, such as the meningeal and choroid plexus macrophages are replaced by new immigrating bone marrow derived cells [163],

While there is a large body of knowledge detailing the role of chemokines in the brain under inflammatory conditions, their role in regulating homeostatic leukocyte immigration into the CNS are ill defined. Nevertheless, the chemokines CCL2/MCP-1 and CX3CL1/Fractalkine are implicated based on their constitutive expression within the CNS [176], The chemokine receptor CXCR4 and its ligand CXCL12/SDF-1 have also been proposed to regulate homeostasis due to their cerebellar expression [1],

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