Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion.
Barnett MH and Prineas JW;
Commented by , 19 Apr 2004
Background
Multiple sclerosis (MS) is considered to be a T-cell mediated autoimmune disease, causing inflammatory demyelination in the CNS. Still, some pathophysiological features can not be explained by this hypothesis, e.g. the extensive oligodendrocytic loss in MS plaques.
Recently it has been reported (Lucchinetti et al. Ann Neurol 2000;47:707-717) that zones of apoptotic oligodendrocytes are predominant in some MS cases, referred to as type 3 lesions, which might represent an early stage in the formation of MS lesions.
Aim
To describe the early clinical and pathological changes in acute and severe MS.
Methods
Autopsy CNS tissue samples from 12 cases with acute lethal MS, and 6 patients with long standing MS selected from an archival bank. The clinical course of one of the lethal MS cases is thoroughly described in the article, being a 14 year old woman with a disease duration of 9 months, who died from a neurogenic pulmonary edema.
Immunostaining was performed using several primary antibodies against macrophage/microglia, complement, different serum proteins, myelin/oligodendrocytes, astrocytes, T lymphocytes, activated T-cells and activated caspase 3.
21 myelin stained sections were sampled showing 6 remyelinating shadow plaques, 1 remyelinating shadow plaque with edge activity, and 5 demyelinating lesions. Seven of the lesions were located in the cerebrum and five in the brainstem. In the 14-year-old case (17-hour lesion), there was relatively little loss of myelin in the fatal brainstem lesion, whereas the appearing oligodendrocytes had characteristic apoptotic features.
Only 2% of the apoptotic oligodendrocytes were immunoreactive for activated caspase 3. Macrophages, T-cells, and activated microglia cells were absent in the lesion. Nine additional lesions similar to the 17-hour lesion were identified in six other cases. No such lesions were found in the six patients with chronic MS.
Discussion
The study suggests a novel pathological mechanism underlying lesion formation in MS, and confirms data from Lucchinetti et al. An initial phase of widespread oligodendrocyte apoptosis is suggested to precede infiltration of T-cells, macrophages, activated microglia and reactive astrocytes. The mechanism leading to the oligodendeocyte apoptosis appears to be independent of caspase 3, although the reliability of this conclusion is weak for methodological reasons.
Several possible theories are suggested by the authors, including viral infection of oligodendrocytes, hypoxic stress and cytokine secretion from activated microglia, although there is no evidence of the cause for the observed changes. Still, the study raises a very important and fundamental question, whether inflammatory demyelination is central in the pathogenesis of MS or just a natural response to tissue destruction. A key issue that has to be answered, in order to understand the pathophysiology of the disease.