Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis.
Ann Neurol
; 73(2): 281-93, 2013 Feb.
Article
em En
| MEDLINE
| ID: mdl-23280437
ABSTRACT
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[IC]), 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(IC)-injected mice.RESULTS:
We demonstrate that dsRNA signaling induced by poly(IC) specifically triggers the overexpression of α-AChR in TECs and not of other TSAs. A poly(IC) 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)-ß. In parallel, human MG thymuses also display an overexpression of TLR3, PKR, and IFN-ß. In addition, poly(IC) 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
RNA de Cadeia Dupla
/
Transdução de Sinais
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Poli I-C
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Miastenia Gravis
Tipo de estudo:
Etiology_studies
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article