1. early disease process
2. environment and genetics
3. clinical trial results.
Here are the early disease process abstracts with what I think are the interesting bits in bold:
Charcot Award Lecture
Friday, September 11, 2009, 09:15 - 10:15
The pathogenesis of relapsing and remitting multiple sclerosis – versions one to five and counting
J. Prineas (Sydney, AU)
Charcot singled out two features in particular that seemed to him most important in understanding the nature of multiple sclerosis - the multifocal, patchy nature of tissue damage, and the fact that myelin was destroyed, leaving axons largely intact.
JW Dawson, writing some fifty years later, added to two important facts, first, that myelin loss was not the result of a slow overgrowth of glial fibres as suggested by Charcot, but that each plaques evolved through a phase of abrupt breakdown of myelin, and second, that such lesions tended to develop around blood vessels. The latter was interpreted as evidence of some noxious factor - a toxin or an enzyme with a propensity to attack myelin - diffusing into the tissue from the blood or perivascular “lymph channels”.
The next important insight into the pathogenesis of the disease was the discovery, by the 1950s, that MS was not the only primary demyelinating disease characterized by perivascular demyelination but was one of a group that included post- infectious encephalomyelitis, rabies post- vaccination encephalomyelitis, and the experimental autoimmune disease discovered in the 1930s, EAE. Subsequent morphological and immunohistochemical studies of inflammatory cells and mediators in affected tissue in MS and in EAE reinforced the idea that these were analogous disorders and that tissue destruction in MS, like that in myelin- induced EAE, was mediated by CD4- positive T cells reactive against a myelin or oligodendrocyte antigen.
The discovery in the 1960s that the adult mammalian CNS had the capacity to remyelinate following experimental demyelination provided the key to the later discovery of an unsuspected dynamic in MS, namely that the destructive phase in individual lesions lasts only a few weeks, following which the lesion exhibits signs of vigorous oligodendrocyte regeneration and the reappearance of new myelin sheaths throughout tissue still packed with macrophage and steeped in IgG. This also introduced the important concept of failed remyelination in MS.
The current view of the newly forming MS lesion is based on a number of recent immunohistochemical studies challenging the idea that myelin loss is orchestrated by antigen-specific CD4+ T cells. These include reports that show that commencing myelin breakdown is preceded by a pre-phagocytic phase characterised by an acute loss of oligodendrocyte perikarya from otherwise intact myelinated tissue and that this occurs largely in the absence of T cells.
There is a strong possibility that the next insight into the pathogenesis of MS will be rooted in what some believe may be the most important breakthrough related to the pathogenesis of MS since the discovery of EAE, namely reports that multifocal demyelination in neuromyelitis optica (NMO) is associated with the presence of a serum antibody directed against astrocytes. As MS and NMO are remarkably similar multifocal, relapsing and remitting demyelinating diseases with demyelination the result of an abrupt loss of both oligodendrocytes and astrocytes , the question that most needs addressing concerns the link that exists between these two diseases.
Pathology of MS
Friday, September 11, 2009, 15:30 - 17:00
The astrocyte lesion in neuromyelitis optica and multiple sclerosis
J. Parratt, J. Prineas (Sydney, AU)
Objective: Recent evidence suggests neuromyelitis optica (NMO), a disease historically regarded as a form of multiple sclerosis (MS), is an autoimmune disease targeting astrocyte endfeet. The present objective was to determine if an astrocyte lesion occurs in MS and whether this is similar to that in NMO.
Methods: Autopsy tissue from 13 patients with NMO and 31 MS patients was examined immunohistochemically for astrocytes, oligodendrocytes and other determinants including aquaporin-4 (AQP4), a water channel protein concentrated in astrocyte endfeet. The fine structure of astrocyte endfeet in MS was determined by electron microscopy.
Results: Early NMO lesions consisted of confluent perivascular sleeves of vacuolar myelinolysis accompanied by an abrupt loss of both astrocytes and oligodendrocytes. Reparative gliosis was effected by small AQP4-negative astrocytes without reformation of astrocyte endfeet or reappearance of oligodendrocytes. Specific for NMO were linear deposits of complement on pial, vascular and root entry zone glial limiting membranes (GLMs). Early MS lesions showed a loss of astrocyte endfeet and some loss of astrocyte perikarya followed by the appearance of large AQP4-positive astrocytes that often reformed vascular endfeet.
Interpretation: Demyelination, oligodendrocyte loss and failure of remyelination in NMO result from destruction of AQP4-expressing astrocytes and endfeet. The presence of degenerative changes in astrocyte endfeet in early MS lesions raises the possibility that demyelination, oligodendrocyte loss and the eventual failure of remyelination in MS may also be a bystander effect of an astrocyte or GLM lesion, and that like NMO, MS is not a disease primarily of oligodendrocytes and myelin.
Pathology of MS
Friday, September 11, 2009, 15:30 - 17:00
Multiple sclerosis: distribution of inflammatory cells in newly forming lesions
A. Henderson, M. Barnett, J. Parratt, J. Prineas (Sydney, AU)
CD4 T cell-dependent macrophage activation directed against a myelin or oligodendrocyte antigen is generally thought to be the mechanism causing myelin destruction in multiple sclerosis. However, areas within expanding MS lesions may exhibit prominent oligodendrocyte loss and apoptosis in the absence of infiltrating lymphocytes. The present study was designed to further investigate the inflammatory profile of different regions within rapidly expanding MS lesions.
Twenty-six active lesions from eleven patients with early MS were serially sectioned and immunostained for T and B cells, plasma cells, ramified microglia, macrophages, monocytes and CD209 positive dendritic cells. Cell counts were compared in pre-phagocytic, phagocytic and immediately postphagocytic areas.
Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes. In contrast, trailing areas of complete demyelination packed with lipid macrophages, and, in some lesions, regenerating oligodendrocytes, showed large numbers of T cells, B cells and IgG positive plasma cells. Lesions in two exceptionally early cases contained relatively few T and B cells, and no IgG positive plasma cells.
Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions. Macrophage activity is largely an innate scavenging response to the presence of degenerate and dead myelin. Adaptive immune activity involving T and B cells is conspicuous chiefly in recently demyelinated tissue, which may show signs of oligodendrocyte regeneration. The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte antigen.