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Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis.
- Source :
-
Annals of neurology [Ann Neurol] 2013 Feb; Vol. 73 (2), pp. 281-93. Date of Electronic Publication: 2012 Dec 31. - Publication Year :
- 2013
-
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.<br />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.<br />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.<br />Interpretation: Because anti-AChR antibodies are highly specific for MG and are pathogenic, dsRNA-signaling activation could contribute to the etiology of MG.<br /> (Copyright © 2012 American Neurological Association.)
- Subjects :
- Adolescent
Adult
Animals
Antibody Specificity
Autoantibodies blood
Autoantibodies immunology
Autoimmunity genetics
Autoimmunity immunology
B-Lymphocytes immunology
Cells, Cultured
Gene Expression drug effects
Gene Expression immunology
Humans
Infant
Interferon Inducers immunology
Interferon Inducers metabolism
Interferon Inducers pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myasthenia Gravis etiology
Poly I-C metabolism
Poly I-C pharmacology
RNA, Double-Stranded metabolism
RNA, Double-Stranded pharmacology
RNA, Messenger genetics
Receptors, Cholinergic genetics
Receptors, Cholinergic immunology
Signal Transduction immunology
Thymus Gland cytology
Young Adult
Myasthenia Gravis genetics
Myasthenia Gravis immunology
Poly I-C immunology
RNA, Double-Stranded immunology
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1531-8249
- Volume :
- 73
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Annals of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 23280437
- Full Text :
- https://doi.org/10.1002/ana.23791