Résumé :
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Myasthenia Gravis (MG) is mainly due to autoantibodies against the nicotinic acetylcholine receptor (AChR) at the postsynaptic membrane that cause loss of functional AChR and disturb neuromuscular transmission. The thymus is clearly involved in the pathogenesis of MG with anti-AChR antibodies, and thymic hyperplasia of lymphoproliferative origin is a hallmark of the disease. Our analysis of the thymic transcriptome of MG patients had provided evidence for a global overexpression of genes regulated by interferon type I (IFN-I), an antiviral and immunomodulatory molecule. As the thymus can be a target organ in infectious diseases, we investigated in detail if pathogen-sensing molecules and the activation of the innate immune system could participate to thymic changes leading to MG development.We demonstrated that among TLR agonists Poly(I:C) by mimicking dsRNA specifically triggered the overexpression of _-AChR in human thymic epithelial cell cultures. This induction of _-AChR was selective compared to other AChR subunits or tissue-specific antigens, and appeared to be independent of the autoimmune regulator AIRE. We then showed that Poly(I:C) effect on _-AChR expression was mediated through toll-like receptor 3 (TLR3) and protein kinase R (PKR) activation, and the release of IFN-I, mainly IFN-b. Similar observations were made in vivo. Indeed, i.p. injections of Poly(I:C) in C57bl/6 wild-type mice increased selectively _-AChR expression in the thymus while this was not observed in IFN-I knockout mice.In parallel, we demonstrated that the thymus of MG patients was characterized by the overexpression of the dsRNA-sensing molecules TLR3, PKR and the RNA helicase RIG1, and that of downstream genes involved in antiviral response, such as IFN-b, myxovirus resistance A (MxA) and 2'5' oligoadlate synthses (OAS). Altogether, these results demonstrate that dsRNA modulates thymic expression of _-AChR though the release of IFN-I, and that an increased signalization through dsRNA-sensing molecules in the thymus could be involved in the etiology of MG.
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