Biomedical subjects
Publications and source records attributed to K van der Maesen.
In a 4-months-old male infant who had been discovered in his bed pale, apnoeic and cold, fundoscopy revealed multiple retinal haemorrhages due to shaken baby syndrome.
To determine if central nervous system (CNS) microvessel endothelial cells express class II major histocompatibility complex (MHC) molecules in early demyelinating lesions in humans, cerebral white matter (WM) biopsies from patients with acute inflammatory/demyelinating conditions, including 4 with multiple sclerosis (MS), were immunostained for class II MHC and other antigens. Eight of 9 biopsies showed focal MHC class II-positive endothelial cells; there were none in the CNS of 1 of the MS patients at autopsy. There were more vessels with class II-positive endothelial cells in areas with intact WM and gliosis than in areas with active demyelination or control WM; class II-positive endothelial cells in small venules and capillaries were adjacent to transmigrating and perivascular CD4-positive cells. By immunoelectron microscopy, class II molecules were localized to vesicles in endothelial cell cytoplasm, suggesting the potential for antigen processing. Perivascular cells, parenchymal microglia, mononuclear cells and the perinuclear cytoplasm but not the processes of astrocytes were also class II-positive. These data indicate that in acute CNS inflammatory/demyelinating lesions, endothelial cells focally and apparently transiently express class II MHC molecules. This expression implies potential antigen-specific interactions, immunoregulatory or signalling functions in endothelial cells, or it may render them susceptible to CD4-positive cell-mediated cytotoxicity. Thus, class II-positive endothelial cells may have pivotal immunologic roles in initial stages of T cell responses in human CNS WM, particularly in acute MS lesions.
Certain cytokines are believed to play a key role in the development of autoimmune demyelinating diseases. Little is known, however, about the effects of these cytokines in the regulation of the key event in myelin destruction, the phagocytosis of myelin by phagocytic cells. We investigated the effects of certain cytokines and growth factors on cultured peritoneal macrophages and microglia in respect to their various functions, phagocytosis, secreted proteolytic activity, and oxidative activity. Interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and lipopolysaccharide (LPS), all proinflammatory factors, actually decreased (IFN-gamma and LPS), or had no effect (TNF-alpha) on myelin phagocytosis by macrophages, but substantially increased phagocytic activity by microglia. Surprisingly, interleukins 4 and 10 (IL-4 and IL-10), considered to be downregulating cytokines, increased phagocytic activity by macrophages, while with microglia, IL-4 had no effect, but IL-10 almost doubled myelin phagocytosis. Transforming growth factor-beta (TGF-beta) had no significant effect on either cell. These cytokines did not affect proteolytic secretion in microglia, while IFN-gamma and LPS induced a doubling of the secreted proteases. This proteolytic activity was almost completely suppressed by calpain inhibitors, although some gelatinase appeared to be present. Microglia exerted much more oxidative activity on the membranes than macrophages, and granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 1beta (IL-1beta) significantly increased microglial oxidative activity. The pattern of responses of macrophages and microglia to the cytokine types indicate that in cytokine-driven autoimmune demyelinating disease, microglia may be the more aggressive cell in causing tissue injury by phagocytosis and oxidative injury, while infiltrating macrophages may produce most of the proteolytic activity thought to contribute to myelin destruction.
Peripheral macrophages infiltrating the central nervous system and resident microglia phagocytize myelin in cell-mediated demyelinating diseases, including experimental autoimmune encephalomyelitis and multiple sclerosis. A cascade of cytokines is believed to modulate the immunological sequence of events occurring in these conditions, and several of these mediate their effects through the protein kinase C pathway. Therefore, we compared the effects of phorbol myristate acetate (PMA), an activator of protein kinase C, on various functions of cultured macrophages and microglia. PMA at moderate concentrations induced apoptosis in macrophages, and this process appeared to be increased in the presence of myelin. In contrast, microglia were activated by PMA, and greatly increased their phagocytosis of myelin. Control macrophages released a considerable amount of proteolytic activity into the medium, as measured by the breakdown of myelin basic protein, and in the process of undergoing apoptosis from PMA-treatment, even higher amounts were released. The enzyme activity in control macrophage medium was inhibited mainly by PMSF and calpain inhibitors, while that from PMA-treated macrophages was inhibited by calpain inhibitors only. An ICE inhibitor was ineffective in inhibiting activity in medium from PMA-treated cells undergoing apoptosis. Medium from microglia contained very little proteolytic activity, and this was not increased by PMA. Cultured macrophages showed little evidence of oxygen free radical release as measured by the TBARS procedure, and PMA had no effect. Microglia, on the other hand, produced higher levels of reactive oxygen species, with a further increase of 18% by PMA. Thus major functions of these phagocytic cells appear to be modulated by the protein kinase C pathway, although the two cell types show very different responses to an activator of this signal.