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

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. ANN NEUROL 2013;73:281–293