Multiple Sclerosis: A Role for Astroglia in Active Demyelination Suggested by Class II MHC Expression and Ultrastructural Study

Abstract

Central nervous system (CNS) tissue was studied by immunocytochemistry and electron microscopy from three cases of multiple sclerosis (MS) in which evidence of ongoing myelin breakdown could be documented. The study focussed upon the role of glial cells in the pathogenesis of demyelination. In acute MS, demyelination involved the vesicular dissolution of myelin from intact axons and a paucity of fibrillary astrogliosis. Foamy macrophages, many of them probably derived from transformed and recently proliferated microglia, contained recognizable myelin debris and lipid droplets and were abundant throughout the lesions. These cells formed the major phagocytic population and stained positively for class II major histocompatibility complex antigens (HLA-DR; Ia). In acute MS lesions, rounded astrocytes were encountered which possessed membrane-bound compartments enclosing phagocytosed fragments of myelin basic protein-positive debris. Despite the superficial resemblance of these cells to foamy macrophages, the presence of intermediate filaments, glycogen granules and diffuse glial fibrillary acidic protein positivity supported an astroglial identity. Astrocyte processes were involved in myelin removal and invested recently demyelinated axons. Hypertrophic fibrous astrocytes were common in chronic active lesions, were capable of myelin degradation and on occasion, contained myelin debris attached to clathrin-coated pits. These astrocytes were sometimes Ia+. Oligodendrocytes were depleted from the center of active lesions but were numerous at the lesion margin, suggesting survival and proliferation. They stained positively for myelin-associated glycoprotein, a marker for immature oligodendrocytes. However, they were invariably Ia-. The findings confirm and further support a role for the astrocyte as both an antigen presenting cell and a phagocyte in the CNS during MS.

Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis

“…Calpain also may be secreted by activated macrophages as are other proteases (38,39). However, intracellular calpain in activated macrophages, such as lipid-laden macrophages observed in MS plaques, may participate in the degradation of myelin engulfed via phagocytosis (40).…”

Astrocytes in the tempest of multiple sclerosis

“…Besides infiltrating cells, microglia and astrocytes contribute to demyelination through phagocytosis of myelin and generation of molecules toxic to olygodendrocytes. The ability of astrocytes to perform phagocytosis of myelin was recorded in acute MS lesions, where hypertrofic astrocytes were identified as cells capable of myelin degradation and internalization of myelin debris through clathrin-coated pits [98]. Regarding toxicity of astrocytic products, for instance syncytin-1 expression in astrocytes leads to the induction of various reactive species, such as superoxide anion and peroxynitrite, to which oligodendrocytes are particularly vulnerable because the level of antioxidants might be lower in this cell type [99].…”

Are Astrocytes Central Players in the Pathophysiology of Multiple Sclerosis?

“…It is therefore difficult to understand why patients with ischemic stroke do not develop inflammatory demyelinating lesions despite the presence of activated T cells against myelin proteins in their circulation. 16 Initial reports [17][18][19][20][21] showing that astrocytes in active MS lesions express class II MHC molecules have been contradicted by a series of observations that failed to confirm these findings. 13,22,23 A recent observation corroborates the initial reports that some scattered astrocytes in active MS lesions, especially at the plaque edges, express MHC class II molecules.…”