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Role of the fibrinolytic system in experimental allergic encephalomyelitis.

East, E.; (2005) Role of the fibrinolytic system in experimental allergic encephalomyelitis. Doctoral thesis , University of London. Green open access

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Abstract

The immunopathology of multiple sclerosis (MS), a disease of the central nervous system (CNS), is characterised by widespread inflammation, focal demyelination and axonal degeneration. As a result of early disturbances in the blood brain barrier (BBB), serum proteins, including fibrin(ogen) enter into the CNS. Up-regulation of components of the plasminogen activator (fibrinolytic) system correlates with onset of inflammation and migration of leucocytes into the brain parenchyma. Significant upregulation of plasminogen and plasminogen activator inhibitor-1 (PAI-1), and an accumulation of fibrin D-dimer was found during neuroinflammation, in the established mouse model of MS, chronic relapsing experimental allergic encephalomyelitis (CREAE) induced with spinal cord homogenate (SCH). Onset and progression of disease correlated with a reduction in dendritic markers, supporting evidence of early neuronal/axonal dysfunction. Furthermore an impairment of fibrinolysis in these mice ensured that fibrin entering the CNS was not effectively removed, suggesting a role for the PA system in the pathogenesis of CREAE. Initially, using mice deficient in tissue-type plasminogen activator (tPA"/") and myelin oligodendrocyte glycoprotein (MOG)-induced EAE, animals displayed an early and a more severe acute disease characterised by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of PAI-1. This correlated with fibrin accumulation, which co-localised with non-phosphorylated neurofilament on thickened axons in EAE tissue. In contrast, urokinase plasminogen activator receptor knockout mice (uPAR"A) had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. However, these animals developed chronic disease as a result of steadily increasing inflammation, high levels of urokinase-type plasminogen activator (uPA) and greater degree of demyelination. Due to low rates of EAE susceptibility, mice deficient for PAI-1 were backcrossed onto the ABH strain for 4 generations. Induction of SCH-CREAE in PAI-1"7" mice resulted in a lower incidence of disease, with mice developing clinical signs of EAE significantly later than WT littermates. A delay in cellular entry into the CNS accompanied by a higher capacity for fibrinolysis resulted in a milder disease in PAI-1"7" mice with no clinical relapses and less axonal damage. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA, PAI-1 and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may be of therapeutic importance in multiple sclerosis.

Type: Thesis (Doctoral)
Title: Role of the fibrinolytic system in experimental allergic encephalomyelitis.
Identifier: PQ ETD:591955
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: http://discovery.ucl.ac.uk/id/eprint/1444646
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