title: Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis.
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[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.
  
  
  CONCLUSIONS
  Because anti-AChR antibodies are highly specific for MG and are pathogenic, dsRNA-signaling activation could contribute to the etiology of MG.
authors.affiliation: Research unit CNRS UMR7215/INSERM U974/UPMC UM76/AIM - Institute of Myology - Therapies of the disorders of striated muscle Pitié-Salpêtrière, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Cufi
authors.forename: Nadine
authors.initials: N
authors.lastname: Dragin
authors.forename: Julia Miriam
authors.initials: JM
authors.lastname: Weiss
authors.forename: Pilar
authors.initials: P
authors.lastname: Martinez-Martinez
authors.forename: Marc H
authors.initials: MH
authors.lastname: De Baets
authors.forename: Régine
authors.initials: R
authors.lastname: Roussin
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.forename: Sonia
authors.initials: S
authors.lastname: Berrih-Aknin
authors.forename: Rozen
authors.initials: R
authors.lastname: Le Panse
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007223:Infant; D007369:Interferon Inducers / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009157:Myasthenia Gravis / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D007369:Interferon Inducers; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D011070:Poly I-C