AbstractsBiology & Animal Science

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. This disease is characterised by the unpredictable occurrence of relapses, defined as an exacerbation of pre-existing symptoms or the appearance of new neurological symptoms. Relapses are separated by periods of remission. Several treatments have been developed to slow down the relapse rate, lesion load progression and to prevent the accumulation of disability. MS relapses can be treated with intravenous injection of methylprednisolone (ivMP), a synthetic glucocorticoid. A dysregulation between pro- and anti-inflammatory pathways could contribute to disease pathogenesis, notably involving interleukin-17 producing T helper lymphocytes (Th17) and regulatory T cells (Tregs). During this thesis, we investigated the cytokine network as well as the Tregs in the context of MS relapses. We further studied their modulation by ivMP and by treatment with fingolimod. We showed that the proportion of Th17 cells increases during MS relapses. Similarly, the mRNA expression of IL-22 is increased in MS patients. Therefore, a deregulation of IL-17- and IL-22-producing cells might exist in MS patients. Although the frequency of Tregs is similar between relapsing MS patients and healthy controls, we observed an increase of Tregs expressing the ectonucleotidase CD39, cells that have been described to inhibit IL-17 production. We studied the impact of the treatment of relapses with ivMP on the cytokine network. Ex vivo, ivMP exerts an inhibitory effect on the mRNA level of the pro-inflammatory cytokines IL-4, IL-6, IL-13, IL-21, IL-23 and IFN-γ. On the contrary, the regulatory cytokines EBI3, IL-10 and TGF-β are increased by the treatment. Moreover, ivMP induces an increase in the proportion of CD39+ Tregs. The main mode of action of fingolimod consists in the retention of lymphocytes within the lymph nodes. Accordingly, we have shown that this treatment decreases the proportion of B cells and CD4+ while CD8+ T cells are less affected. Besides this, it is now clear that fingolimod could mediate additional effects. Indeed, we have shown that it also induces an increase of CD39+ Tregs. In conclusion, our data, in agreement with the literature, confirm the activation of pro-inflammatory pathways during MS relapses. We have also shown the activation of immune-regulatory pathways. IvMP and fingolimod both favor those regulatory pathways which could, at least in part, mediate their therapeutic benefit. La sclérose en plaques (SEP) est une maladie inflammatoire chronique du système nerveux central. Cette pathologie est caractérisée par la survenue imprévisible de poussées, définies par l’exacerbation ou l’apparition de nouveaux symptômes neurologiques, espacées de périodes de rémission. Certains traitements de fond ont été développés afin de ralentir la fréquence des poussées, la progression de la charge lésionnelle et de prévenir l’accumulation du handicap. Les poussées peuvent être traitées par injection intraveineuse de méthylprednisolone, un…