Multiple sclerosis (MS) was recognized by the mid 19th century, and already in 1871 Hammond referred to it as a cerebrospinal sclerosis; it was Charcot who, in 1877, realized the role of disrupted myelin in the pathogenesis of this disease. MS is an inflammatory demyelinating disease of the CNS, which culminates in progressive neurological deterioration. The aetiology of MS remains elusive, as both genetic predisposition and environmental factors are indicated. The importance of genetic predisposition is evident from very high concordance of the disease occurrence between monozygotic twins, whereas the environmental factors are implicated by the existence of geographical areas with remarkable differences in MS prevalence (generally, MS is significantly more frequent in northern than in southern parts of the world). The general theory regards MS aetiology as an infection which presents the immune system with an antigen similar to CNS myelin; the resulting antibodies eventually attack CNS myelin and cause demyelination. This theory, however, is very broad and imprecise, as indeed MS can cover several aetiologically distinct diseases with similar pathological endpoint and clinical features.
Indeed, the pathogenesis of MS shows several distinct demyelinating patterns. The first group of MS lesions are characterized by preferential destruction of myelin complemented by local inflammation; which results, most likely, from an autoimmune reaction, and is not associated with significant oligodendrocyte death; this type of MS is characterized by well pronounced remyelination manifested by clinical remissions. The second type of MS progression is associated with oligoden-drocyte death, which may happen either through apoptosis or necrosis. This form of MS progression is more violent, and patients with necrotic oligodendrocyte death are diagnosed with the so-called 'primary progressive' disease which does not show any relapses, and severe neurological deterioration. Moreover, the apoptotic death of oligodendrocytes has begun to be considered as the key step in initiation of MS pathological development, which may precede the autoimmune attack.
Importantly, however, in both types of disease pathogenesis, the areas of demyelination always show the signs of inflammatory processes and are rich in activated T lymphocytes. The latter can in fact cross the blood-brain barrier, and can attack the antigen-presenting tissue, which in the case of MS are myelin components or some parts of oligodendrocytes or both. At the same time, MS is accompanied with a degree of microglia activation; the activated microglia may be involved in regulating/shaping the immune response and somehow affecting the course of demyelination/oligodendrocyte death. Yet, the actual mechanisms which determine the progression of MS, and the role of different cellular elements in it, remains unresolved. Particularly interesting is the question of the initiation of oligodendroglial death, which can involve the Ca2+ toxic route; there are some indications that incubation of oligodendrocytes with antibodies to myelin-oligodendrocyte glycoprotein triggers [Ca2+]j elevations and activation of intracellular kinases. Glutamate-mediated Ca2+ dependent excitoxicity is also indicated in oligodendrocyte loss in MS.
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