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Article Dans Une Revue Annals of Neurology Année : 2013

Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis

Résumé

Objective: Myasthenia gravis (MG) is an autoimmune disease mediated mainly by anti-acetylcholine receptor (AChR) antibodies. The thymus plays a primary role in MG pathogenesis. As we recently showed an inflammatory and antiviral signature in MG thymuses, we investigated whether pathogen-sensing molecules could contribute to an anti-AChR response. Methods: We studied the effects of toll-like receptor agonists on the expression of α-AChR and various tissue-specific antigens (TSAs) in human thymic epithelial cell (TEC) cultures. As polyinosinic-polycytidylic acid (poly[I:C]), which mimics double-stranded RNA (dsRNA), stimulated specifically α-AChR expression, the signaling pathways involved were investigated. In parallel, we analyzed the expression of dsRNA-signaling components in the thymus of MG patients, and the relevance of our data was investigated in vivo in poly(I:C)-injected mice. Results: We demonstrate that dsRNA signaling induced by poly(I:C) specifically triggers the overexpression of α-AChR in TECs and not of other TSAs. A poly(I:C) effect was also observed on MG TECs. This induction is mediated through toll-like receptor 3 (TLR3) and protein kinase R (PKR), and by the release of interferon (IFN)-β. In parallel, human MG thymuses also display an overexpression of TLR3, PKR, and IFN-β. In addition, poly(I:C) injections specifically increase thymic expression of α-AChR in wild-type mice, but not in IFN-I receptor knockout mice. These injections also lead to an anti-AChR autoimmune response characterized by a significant production of serum anti-AChR antibodies and a specific proliferation of B cells. Interpretation: Because anti-AChR antibodies are highly specific for MG and are pathogenic, dsRNA-signaling activation could contribute to the etiology of MG.

Dates et versions

hal-03442085 , version 1 (22-11-2021)

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Citer

Perrine Cufi, Nadine Dragin, Julia Miriam Weiss, Pilar Martinez-Martinez, Marc de Baets, et al.. Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis. Annals of Neurology, 2013, 73 (2), pp.281-293. ⟨10.1002/ana.23791⟩. ⟨hal-03442085⟩
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