Le rôle des cytokines et des molécules d'adhérence cellulaire dans la formation des lésions de la sclérose en plaques.

Abstract

La sclérose en plaques est une maladie démyélinisante inflammatoire chronique qui atteint de façon sélective la myéline du système nerveux central. L’étiologie de cette maladie neurologique – fréquente – demeure inconnue. L’hypothèse selon laquelle une réponse immune aberrante serait à l’origine des plaques de démyélinisation, ainsi que des lésions axonales, est couramment admise. Un stimulus de l’environnement, tel qu’une infection virale non spécifique, pourrait déclencher cette réponse immunitaire, chez un individu ayant déjà une susceptibilité génétique à la maladie. L’étude des mécanismes moléculaires impliqués dans cette cascade immunologique a permis de mettre au point certains traitements immunomodulateurs comme les interférons β ; ils diminuent la progression de cette maladie pour laquelle aucun traitement étiologique ne s’était avéré efficace. La compréhension des mécanismes immunologiques impliqués dans la sclérose en plaques permet maintenant d’envisager des traitements mieux ciblés.

It is increasingly clear that there is a strong autoimmune component to the pathogenesis of multiple sclerosis (MS) plaques. Population and multiplex family studies indicate an immunogenetic susceptibility to MS. Genetic factors play only a partial role in the etiology. Non genetic factors, as yet undetermined, must intervene in the process. The initiating event in MS would be the clonal expansion, in the periphery (possibly in response to a non specific incidental infection), of T-cell lines specific for proteins of myelin. These lymphocytes, when activated, can gain access to the central nervous system, through the blood-brain barrier, by way of the cellular adhesion molecules, which allow the lymphocytes to adhere to the endothelial cells and cross the barrier. They are subsequently presented to the target antigen(s) by perivascular cells, parenchymal cells, or macrophages which have previously invaded the central nervous system, along with the appropriate HLA molecules, thus forming, with the T-cell antigen receptor, a trimolecular complex. Cytokines are then activated; they can amplify, or dampen, the immune response. Subsequently, additional inflammatory cells are recruited. Activated inflammatory cells, as well as glial cells, produce cytokines, which can regulate the immune response, or directly induce injury of myelin and the oligodendrocyte, its synthesizing cell. T-cells can be divided in two classes, based on their cytokine profiles: Th-1 cells produce proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma; Th-2 cells secrete anti-inflammatory cytokines, such as interferon beta and IL-10. Th-1 cells are the mediators of the animal model of MS, experimental allergic encephalomyelitis. Th-2 cells may be disease protective. New treatments, interferons and copolymer-1, probably act by promoting Th-2 cells, or by counteracting Th-1 cells, or their products. The better understanding of the immunology of the MS plaque should soon lead to therapies that could prevent the formation, or the growth, of plaques, even before the etiology of MS is elucidated. [References: 30]