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Implication of microRNAs in the pathophysiology of autoimmune Myasthenia Gravis

Abstract : Autoimmune Myasthenia Gravis (MG), characterized by autoantibodies directed against the acetylcholine receptor at the neuromuscular junction, is a rare disease causing muscular weaknesses. This study shows the involvement of small non coding RNAs, miRNAs, in the pathophysiology of MG. We investigated the expression of dysregulated miRNAs in the effector organ of the disease, the thymus, through a miRnome analysis. I showed 1) that miR-7-5p could participate in thymic abnormalities observed in patients through its action on CCL21, 2) the down-regulation of two miRNA clusters on chromosome X and, 3) a new MG inflammatory pathway involving miR-125a-5p and WDR1. I also studied the sensitivity of miR-29a KO mice to the experimental model of MG. Indeed, miR-29a is down-regulated in MG thymuses and modulates type 1 interferon pathway, involved in thymic changes. Finally, I investigated the causes and consequences of the serum overexpression of miR-150-5p, characterized as a biomarker in MG. We showed that miR-150 is overexpressed in MG thymuses and correlated to the presence of ectopic germinal centers. Moreover, miR-150 is down-regulated in CD4+T cells, in the blood of patients. Once in the serum, miR-150 modulated the expression of target genes, such as MYB, and is involved in the survival of CD4+ and CD8+ T cells. These studies allows a better understanding of how miRNAs are involved in the pathophysiology of MG and allowed us to open new research avenues in MG.
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  • HAL Id : tel-02613807, version 1

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Mélanie Cron. Implication of microRNAs in the pathophysiology of autoimmune Myasthenia Gravis. Immunology. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS395⟩. ⟨tel-02613807⟩

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