Li, Hong; (1995) Distribution and phenotypic characteristics of mononuclear phagocytes in multiple sclerosis plaques. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by phagocytosis and degradation of myelin by macrophages in active plaques. Macrophages and microglia, the resident macrophage in the CNS, have been characterized by quantitative immunocytochemistry and histochemistry in relation to stages in the evolution of the MS plaque. Active MS plaques have been classified into four groups based on the degree of myelin loss and the neutral lipids within phagocytes. In Group 1 active plaques, defined as early lesions with neutral lipid-containing phagocytes but no detectable myelin loss, the predominant cell type expressing HLA class II-DQ as well as HLA-DR and mature macrophage antigen 25F9 was the microglia, identified by a microglial enzyme marker nucleoside diphosphatase. These cells also contained fragments displaying neoepitopes of myelin basic protein (MBP) and exhibited moderate acid phosphatase but not nonspecific esterase, a monocyte/macrophage enzyme marker. With partial or complete myelin loss in lesions, active plaques were further classified as Groups 2, 3 and 4, respectively, in which the number of macrophages expressing nonspecific esterase and macrophage differentiation antigens Ber-MAC3, RFD7 and RM3/1 increased. These observations provide new evidence that microglia activation occurs early in the course of the disease, and suggest that haematogenous macrophages infiltrate MS plaques at a later stage in their evolution. In order to study macrophage phenotypes in the cerebrospinal fluid (CSF) a method has been developed to prepare CSF cells for cryostat sectioning to enable analysis of multiple markers on samples with low cell numbers. Macrophages in the CSF from either the subarachnoid space or ventricles of postmortem MS and normal control cases exhibited the phenotype of mature macrophages (25F9+, RM3/1+ and Ber-MAC3+) to a greater extent than monocytes in peripheral blood. A similar pattern was observed in living patients with MS or other neurological diseases. In postmortem MS cases, the number of lipid-laden macrophages in the ventricular CSF was significantly higher than in the subarachnoid space or the ventricles of normal controls. There was a positive correlation between the number of lipid-laden macrophages in the ventricles and the number of active plaques from the same case, suggesting an association between the two compartments. Focal loss of endothelial alkaline phosphatase activity and the presence of plasma low density lipoprotein (LDL) in Group 1 active plaques and inflammatory foci of acute experimental allergic encephalomyelitis in Lewis rats are indicative of blood- brain barrier damage. The co-localization of epitopes of oxidized LDL and MBP peptides within a proportion of lipid-laden macrophages in early active MS plaques suggests that uptake of both LDL and myelin contributes to foamy macrophage formation and may be of significance in the pathogenesis of MS.

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