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Inflammatory Cascades in the Pathogenesis of Multiple Sclerosis Lesions

Gveric, Djordje; (1999) Inflammatory Cascades in the Pathogenesis of Multiple Sclerosis Lesions. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Multiple sclerosis (MS) is a disease of the human central nervous system (CNS) characterised by inflammation and demyelination. Initially the MS lesion has a distinct histopathological picture with myelin-positive microglia in the midst of apparently intact myelin but minimal perivascular inflammation. Inflammatory mediators produced by these activated microglia may precipitate the infiltration of mononuclear cells and the overt myelin loss seen in actively demyelinating MS lesions. Nuclear factor-κB (NF-κB) is a transcriptional regulator of proteolytic enzymes, adhesion molecules and inflammatory cytokines which rapidly translates extracellular signals into protein synthesis. The immunocytochemical detection of the transcriptionally active form of NF-κB, but not the inhibitory protein IκBα, in the nuclei of microglia in normal human CNS white matter indicates the capability of microglia to respond rapidly to pathological stimuli in the CNS. Activation of NF-κB in MS plaques, evident from the nuclear localisation of the NF-κB subunits RelA, c-Rel and p50 in macrophages, may propagate inflammatory demyelination through upregulation of NF-κB-controlled macrophage genes for inflammatory mediators. In demyelinating disease the plasmin-matrix metalloprotease (MMP) enzymatic cascade promotes blood-brain barrier (BBB) damage, generation of encephalitogenic myelin peptides and activation of pro-inflammatory cytokines. Constitutive expression of MMPs 1, 2, 3 and 9 in glial cells in normal control white matter was demonstrated by immunocytochemistry. However, the lack of tissue (t-PA) and urokinase (u-PA) plasminogen activators in glial cells and the absence of caseinolytic activity as shown by in situ zymography emphasises the latent nature of the plasmin-MMP cascade in normal CNS tissue. In contrast, the co-localisation of t-PA and u-PA, rate-limiting serine-proteases, and MMPs in macrophages and astrocytes in active MS lesions forms the basis of a functional enzymatic cascade. Furthermore, increased amounts and activity of u-PA and MMP-9 in homogenates of active MS plaques coupled with the presence of caseinolytic activity in foamy macrophages implicates these cells as the major source of MMPs, which cause proteolytic damage in MS. Insulin-like growth factors (IGFs) play an important role in development and myelination in the CNS but can also stimulate phagocytosis and production of inflammatory mediators by macrophages. In active MS lesions binding of IGF-II to the IGF receptor on foamy macrophages may induce mitogenic responses and invasiveness of macrophages which can be further enhanced by MMP-mediated proteolytic removal of inhibitory IGF-binding proteins. Similarly, the potent mitogens IGF-I and insulin may stimulate astrocytosis and gliosis. In contrast, oligodendrocytes in normal-appearing white matter do not express IGFs or IGF-I receptor which implies that the oligodendrocyte response to these remyelinating growth factors is impaired. Therefore, the prevailing role of IGFs in MS lesions may be in line with pro-inflammatory mediators promoting macrophage and astrocyte responses to tissue damage. In conclusion, NF-κB activation in microglia and macrophages upregulates the production of PAs and inflammatory cytokines which trigger the plasmin-MMP cascade, leading to BBB damage and enhanced inflammatory cell migration and demyelination in white matter. Influx of IGFs through the damaged BBB and their increased local production may promote myelin phagocytosis and reactive astrocytosis. In turn IGF-mediated upregulation of PAs in glial cells could provide a feedback amplification of the MMP cascade. Therefore, the findings from these studies bring together three systems of mediators, NF-κB, MMPS and IGFs, into a hypothetical model for the propagation of demyelination in MS lesions.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Inflammatory Cascades in the Pathogenesis of Multiple Sclerosis Lesions
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10123342
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