Oligodendrocytes and the early multiple sclerosis lesion

Abstract

There is little agreement among neuropathologists regarding the timing and nature of oligodendrocyte loss in multiple sclerosis (MS). This review describes changes that accompany acute oligodendrocyte loss in new lesions. Included is a description of the immunopathology of new lesions in 23 severe early cases selected from a bank of 300 MS autopsies. Oligodendrocytes in prephagocytic lesions exhibit cytopathic changes that include apoptosis of oligodendrocytes immunoreactive for caspase 3, phagocytosis of apoptotic oligodendrocytes, swelling of cells with abnormal nuclei, complement deposition, and lysis. These are nonspecific changes that provide no clue as to the cause of oligodendrocyte injury. Associated changes include the presence of enlarged immunoglobulin (IgG)(+) microglia and early macrophages, the presence nearby of a focus of inflammatory demyelination, an open blood-brain barrier, and the presence of rare CD8 T cells. Myelin contacted by IgG(+) macrophages is immunoreactive for complement but not for IgG. It is likely that macrophage activity in evolving white and gray matter plaques is scavenging activity directed at nonvital myelin secondary to oligodendrocytes loss. One feature of MS that is not understood is the extraordinarily close resemblance the disease shows pathologically to neuromyelitis optica (NMO), including that demyelination in both is secondary to a loss of caspase 3-positive apoptotic oligodendrocytes. These similarities raise the possibility that like NMO, MS is an autoimmune disease in which oligodendrocyte apoptosis is determined by injury to some other glial or mesenchymal component.

An initial top-down proteomic analysis of the standard cuprizone mouse model of multiple sclerosis

“…However, as recently discussed, this aetiology remains speculative [1][2][3][4]. As with other CNS diseases, there are multiple issues confounding direct research, and thus, understanding the mechanism(s) underlying this disease has been challenging.…”

Magnetic resonance imaging of experimental autoimmune encephalomyelitis in the common marmoset

“…This is also observed in marmoset EAE (Jordan et al, 1999), where acute lesions are associated with profound leakage of the blood brain barrier (BBB) allowing inflammatory cells and factors to enter the lesion parenchyma (Hart et al, 1998;Maggi et al, 2014a;Katz et al, 1993). In the parenchyma surrounding the central inflamed blood vessel, myelin is usually damaged and picked up from large activated macrophages, exactly as in MS (Hart et al, 1998;Maggi et al, 2014a;Prineas and Parratt, 2012). Both in MS and marmoset EAE (Jordan et al, 1999) new inflammatory lesions detected from Gd based MRI, are mainly associated to extensive demyelination with relative sparing of the axons, whereas older lesions are characterized by markedly reduced inflammatory activity associated to various degree of axonal damage (Hauser, 2015;Jordan et al, 1999;Hart et al, 1998).…”

“…Exactly as in MS early marmoset EAE lesions are demyelinated, can occur both in WM and GM and show Dawson's finger like site and shape, tending to develop around parenchymal veins, (Adams and Kubik, 1952;JM., 1868). A classic feature of early MS lesions, commonly known as acute lesions, is the presence of a cuff of inflammatory cells (mostly lymphocytes and dendritic cells) around the central vein (Prineas and Parratt, 2012). This is also observed in marmoset EAE (Jordan et al, 1999), where acute lesions are associated with profound leakage of the blood brain barrier (BBB) allowing inflammatory cells and factors to enter the lesion parenchyma (Hart et al, 1998;Maggi et al, 2014a;Katz et al, 1993).…”

Multiple sclerosis: Serum anti-CNS autoantibodies

“…There are alternative explanations regarding myelin destruction in MS that do not invoke anti-myelin antibodies-the most plausible, phagocytosis of myelin by activated microglia and monocyte-derived macrophages via scavenger and complement receptors of myelin opsonized by complement secondary to activated caspase 3 oligodendrocyte apoptosis. 34,35 In summary, anti-CNS autoantibodies of diverse specificities are detectable by IIF in sera from approximately one in four patients with MS. These antibodies appear not to differ from serum antibodies detectable in some patients with unrelated diseases of the CNS and in some healthy controls.…”