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Mechanisms of myelin degradation in multiple sclerosis

Owen, Samantha Jane; (1994) Mechanisms of myelin degradation in multiple sclerosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The role of T cells and their products in the pathology of multiple sclerosis (MS) has been studied. A quantitative method has been used to investigate the breakdown of cell free human myelin in vitro. The assay measures the release of 2';3' cyclic nucleotide 3'-phosphodiesterase (CNPase), an intrinsic myelin component. Sera from MS and other neurological diseases (OND) patients was generally devoid of any myelin degradative activity. However, peripheral blood mononuclear cells (PBMC) from 42% (41/97) of MS patients caused significant losses of CNPase activity from the myelin as did PBMC from 58% (15/26) of control patients with, another organ-specific autoimmune disease, rheumatoid arthritis (RA). No correlation was seen in the MS group between in vitro cellular myelin degradative activity and disease status. Significant myelin degradation by cells occurred with only 10% (2/20) of OND PBMC samples and with none of the healthy control samples (n=30). To further investigate the factor(s)/mechanism responsible for in vitro myelin degradation by MS PBMC the possibility that loss of CNPase activity was caused by activated T cells was investigated. Expression of the activation markers, interleukin-2 (IL-2) receptor and MHC class II antigen (HLA-DR) was measured. No correlation was apparent between activation of cells and loss of CNPase activity caused by these cells. Cell supernatants from unstimulated, mitogen stimulated (PHA and Con-A) and antigen stimulated (human myelin basic protein and tuberculin purified protein derivative) MS PBMC were generally unable to cause myelin degradation. The possibility of direct cytokine involvement in myelin damage was investigated by addition of recombinant cytokines to myelin but, no significant loss in CNPase activity was seen. A possible relationship between myelin basic protein (MBP) T cell reactivity (as measured by thymidine incorporation) and cellular myelin degrading activity was also investigated- however, no correlation was seen. Therefore two human MBP specific T cell lines derived from a healthy donor and an MS patient were added to myelin in the presence of autologous antigen presenting cells to see whether myelin antigen specific cells were capable of myelin damage in vitro. Neither of the cell lines caused a significant loss of CNPase activity from myelin. Finally, in order to identify the cell type(s) required for in vitro myelin degradation, the T cell population was enriched and added to myelin with or without autologous macrophages. Macrophages alone at a concentration similar to that observed in a PBMC sample were unable to cause a significant loss in CNPase activity of the myelin. However, when an enriched population of T cells was added, significant myelin degradation was observed. Preliminary experiments investigating serine esterase (SE) expression by MS and healthy individuals' PBMC showed that there was an increase in the number of MS CD8+ lymphocytes expressing SE after 24 h incubation with myelin. The expression of SE by healthy individuals' CD8+ lymphocytes did not change after incubation with myelin. In this thesis, I aim to test the hypothesis that the myelin degrading activity seen with both MS and RA PBMC is a non-specific cellular response shown by chronically activated immune cells or their products occurring in chronic inflammatory autoimmune diseases, and is not confined to MS.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Mechanisms of myelin degradation in multiple sclerosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10101459
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