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Original Article

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

  1. Perrine Cufi MSc1,
  2. Nadine Dragin PhD1,
  3. Julia Miriam Weiss PhD1,
  4. Pilar Martinez-Martinez PhD2,
  5. Marc H. De Baets MD, PhD2,
  6. Régine Roussin MD3,
  7. Elie Fadel MD3,
  8. Sonia Berrih-Aknin PhD1,
  9. Rozen Le Panse PhD1,*

Article first published online: 31 DEC 2012

DOI: 10.1002/ana.23791

Issue

Annals of Neurology

Annals of Neurology

Volume 73, Issue 2, pages 281–293, February 2013

Additional Information

How to Cite

Cufi, P., Dragin, N., Weiss, J. M., Martinez-Martinez, P., De Baets, M. H., Roussin, R., Fadel, E., Berrih-Aknin, S. and Le Panse, R. (2013), Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis. Ann Neurol., 73: 281–293. doi: 10.1002/ana.23791

Author Information

  1. 1

    Research unit (CNRS UMR7215/INSERM U974/UPMC UM76/AIM) – Institute of Myology – Therapies of the disorders of striated muscle Pitié-Salpêtrière, Paris, France

  2. 2

    Department of Neuroscience, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands

  3. 3

    Department of Cardiac Surgery, Marie Lannelongue Hospital, Le Plessis-Robinson, France

*Address correspondence to Dr Le Panse, UMR–CNRS UMR7215/INSERM U974/UPMC UM76/AIM Thérapie des maladies du muscle strié, Groupe hospitalier Pitié-Salpêtrière, 105, boulevard de l'Hôpital, 75651 Paris Cedex 13, France. E-mail: rozen.lepanse@upmc.fr

Publication History

  1. Issue published online: 22 MAR 2013
  2. Article first published online: 31 DEC 2012
  3. Accepted manuscript online: 29 OCT 2012 03:03AM EST
  4. Manuscript Accepted: 13 OCT 2012
  5. Manuscript Revised: 28 SEP 2012
  6. Manuscript Received: 3 OCT 2011

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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

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