The role of the CNS endothelium in the pathogenesis of multiple sclerosis.

PLUMB, Jonathan. (2005). The role of the CNS endothelium in the pathogenesis of multiple sclerosis. Doctoral, Sheffield Hallam University (United Kingdom)..

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Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) causing neurological disability in young adults. The neuropathological features of MS include large perivascular inflammatory cell infiltrates, microglia activation, antigen presentation and reactive astrogliosis. The CNS is protected by highly regulated blood-brain barrier (BBB) that is breached in MS as detected by MRI. Formation and regulation of the BBB involves the interactions of the interendothelial tight junction-associated proteins, occludin, ZO-1 and claudin. The results from this study suggest that the BBB is disrupted at the molecular level with alterations in ZO-1 and occludin expression being observed in blood vessels from MS tissue compared with normal control white matter. Tight junction (TJ) disruption was observed predominantly within vessels from active MS lesion however disruption was also observed within the normal appearing white matter and chronic lesions. The results of this study suggest that TJ disruption plays a critical in disease progression as TJ abnormalities were observed in conjunction with serum protein leakage and large inflammatory infiltrates. BBB leakage as gauged by MRI is reported to cease after an attack however this study shows that a low level of persistent serum protein leakage occurs in chronic lesions.The recruitment of circulating leukocytes and resident glial cells to sites of CNS inflammation is dependant on the interaction of adhesion molecules, chemokines and their receptors and cytokines and their receptors. A disintegrin and metalloproteinase-17 (ADAM-17) is an enzyme that has been shown to mediate proteolytic cleavage of some of these inflammatory components. The results in this study have described the constitutive expression of ADAM-17 by the cerebral endothelial cells in human and rat CNS. ADAM-17 is also shown to be expressed by resident glia and inflammatory cells and is elevated in active MS lesions and in the spinal cords of rats during peak phase of experimental autoimmune encephalomyelitis suggesting a pathogenic role for ADAM-17 in these disease processes. In vitro studies confirmed the production of ADAM-17 by cerebral endothelial cells and astrocytes. ADAM-17 expression is increased under pro-inflammatory conditions whereas its natural inhibitor TIMP3 is decreased. Release of TNF from GP8 cell surface is induced following treatment with TNF and LPS.

Item Type: Thesis (Doctoral)
Contributors:
Thesis advisor - Woodroofe, Nicola
Thesis advisor - Bunning, Rowena [0000-0003-3110-0445]
Additional Information: Thesis (Ph.D.)--Sheffield Hallam University (United Kingdom), 2005.
Research Institute, Centre or Group - Does NOT include content added after October 2018: Sheffield Hallam Doctoral Theses
Depositing User: EPrints Services
Date Deposited: 10 Apr 2018 17:21
Last Modified: 03 May 2023 02:05
URI: https://shura.shu.ac.uk/id/eprint/20237

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