Multiple Sclerosis Lesions - 5

Background
A Serum AntiBody directed against Astrocytes is present in a high proportion of patients with NeuroMyelitis Optica (NMO).

The pathogenicity of the AntiBody is uncertain because no consistent Astrocyte lesion is known to occur in NMO.

Objective
To determine whether there is an Astrocyte lesion in NMO and if this differs from Astrocyte changes in Multiple Sclerosis (MS).

Methods
Astrocyte pathology in early (Still-Myelinated) lesions and subacute NMO and MS lesions was examined ImmunoHistoChemically and in sections stained for Astrocytes using routine Histological techniques.

Results
DeMyelination in early NMO lesions is accompanied by Oligodendrocyte Apoptosis in a pattern identical to that seen in MS and this is preceded by an abrupt destruction of PeriVascular Astrocytes.

Reparative Astrogliosis is effected by a population of unipolar, new Astrocytes. Evidence of a different type of Astrocyte lesion was found in MS.

Discussion
The findings add to experimental evidence that the AntiBody is pathogenic.

They also raise the possibility that DeMyelination in MS may be a bystander effect of an Astrocyte lesion, i.e. that MS is not a disease primarily of Myelin and Oligodendrocytes.

Objective
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 (MS).

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.

Methods
Twenty-six active lesions from 11 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 PrePhagocytic, Phagocytic, and immediately PostPhagocytic areas.

Results
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 ImmunoGlobulin G (IgG)-positive Plasma Cells.

Lesions in 2 exceptionally early cases contained relatively few T and B-Cells, and no IgG-positive Plasma Cells.

Interpretation
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.

NeuroPathological studies of early Multiple Sclerosis (MS) tissue have shaped prevailing views of the pathogenesis of the disease.

The hallmark of the acute MS lesion, inflammatory DeMyelination, has been largely accepted as evidence of a Macrophage-mediated attack on normal Myelin.

Driven by PeriVascular and Parenchymal AutoReactive CD4⁺ Th1-Cells primed in the periphery by an unknown self or foreign Antigen(s).

Predicated largely upon comparisons with Experimental Allergic Encephalomyelitis, this paradigm has, in recent years, been recognized.

As a simplification of the events that constitute and perhaps presage lesion formation in the human disease.

And the importance of the Innate Immune Cells of the Central Nervous System, Humoral Factors, CytoToxic CD8⁺ T-Cells and regulatory T-Cells has been emphasized.

An influential series of publications by one group, based on Histopathological examination of actively DeMyelinating lesions in selected autopsy and biopsy MS tissue, defined four early lesion subtypes.

In a given individual, these subtypes were reported to be mutually exclusive, suggesting that disparate pathogenetic pathways separate patients with clinically indistinguishable syndromes.

This schema, which has considerable therapeutic implications, has not been independently verified.

And has recently been questioned by the finding of a uniform Pre-Phagocytic pathology and overlap of lesion subtypes in individual patients with typical Relapsing/Remitting disease.

The latter findings would suggest that the heterogeneous features observed in active MS lesions.

And sampled at different time-points are a reflection of the evolution of a single PathoPhysiological process, perhaps modified in part by genetic factors in individual cases.