, Volume 36, Issue 1, pp 121–130 | Cite as

Possible Involvement of Toll-Like Receptors in the Pathogenesis of Myasthenia Gravis

  • Yu-Zhong Wang
  • Mei Yan
  • Fa-Fa Tian
  • Jun-Mei Zhang
  • Qun Liu
  • Huan Yang
  • Wen-Bin Zhou
  • Jing Li


Toll-like receptors (TLRs), the innate immunity components, have been demonstrated to participate in multiple autoimmune diseases. However, our knowledge of the roles of TLRs in myasthenia gravis (MG) is still scarce. In this study, we detected the mRNA expression of TLR1 to TLR10 in peripheral blood mononuclear cells (PBMCs) of MG patients and the healthy controls by quantitative real-time polymerase transcription chain reaction. Our data demonstrate that aberrant expressions of TLRs exist in the PBMCs of MG patients and of the total, expression level of TLR9 mRNA has significantly positive relation with the clinical severity of MG, which suggests that TLRs may be involved in the pathogenesis of MG.


myasthenia gravis Toll-like receptors innate immunity 



This work was supported by the National Natural Science Foundation of China (30971033).

Conflict of Interest

The authors declare no competing financial interests.


  1. 1.
    Conti-Fine, B.M., M. Milani, and H.J. Kaminski. 2006. Myasthenia gravis: past, present, and future. The Journal of Clinical Investigation 116: 2843–2854.PubMedCrossRefGoogle Scholar
  2. 2.
    Lindstrom, J.M., M.E. Seybold, V.A. Lennon, S. Whittingham, and D.D. Duane. 1976. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 26: 1054–1059.PubMedCrossRefGoogle Scholar
  3. 3.
    Hoch, W., J. McConville, S. Helms, J. Newsom-Davis, A. Melms, and A. Vincent. 2001. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nature Medicine 7: 365–368.PubMedCrossRefGoogle Scholar
  4. 4.
    McGettrick, A.F., and L.A. O'Neill. 2007. Toll-like receptors: key activators of leucocytes and regulator of haematopoiesis. British Journal of Haematology 139: 185–193.PubMedCrossRefGoogle Scholar
  5. 5.
    Zarember, K.A., and P.J. Godowski. 2002. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. The Journal of Immunology 168: 554–561.PubMedGoogle Scholar
  6. 6.
    Takeda, K. and S. Akira. 2007. Toll-like receptors. Current Protocols in Immunology. Chapter 14: Unit 14 12.Google Scholar
  7. 7.
    Kawai, T., and S. Akira. 2007. TLR signaling. Seminars in Immunology 19: 24–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Medzhitov, R., P. Preston-Hurlburt, E. Kopp, A. Stadlen, C. Chen, S. Ghosh, and C.A. Janeway Jr. 1998. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Molecular Cell 2: 253–258.PubMedCrossRefGoogle Scholar
  9. 9.
    Devaraj, S., M.R. Dasu, J. Rockwood, W. Winter, S.C. Griffen, and I. Jialal. 2008. Increased Toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. The Journal of Clinical Endocrinology and Metabolism 93: 578–583.PubMedCrossRefGoogle Scholar
  10. 10.
    Ehlers, M., H. Fukuyama, T.L. McGaha, A. Aderem, and J.V. Ravetch. 2006. TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. The Journal of Experimental Medicine 203: 553–561.PubMedCrossRefGoogle Scholar
  11. 11.
    Zeuner, R.A., K.J. Ishii, M.J. Lizak, I. Gursel, H. Yamada, D.M. Klinman, and D. Verthelyi. 2002. Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis and Rheumatism 46: 2219–2224.PubMedCrossRefGoogle Scholar
  12. 12.
    Deng, Y.N., and W.B. Zhou. 2007. Expression of TLR4 and TLR9 mRNA in Lewis rats with experimental allergic neuritis. Neuroimmunomodulation 14: 337–343.PubMedCrossRefGoogle Scholar
  13. 13.
    Wang, Y.Z., Q.H. Liang, H. Ramkalawan, Y.L. Wang, Y.F. Yang, W.B. Zhou, F. Tian, J. Li, and H. Yang. 2012. Expression of Toll-like receptors 2, 4 and 9 in Patients with Guillain-Barré syndrome. Neuroimmunomodulation 19: 60–68.PubMedCrossRefGoogle Scholar
  14. 14.
    Wang, Y.Z., Q.H. Liang, H. Ramkalawan, W. Zhang, W.B. Zhou, B. Xiao, F.F. Tian, H. Yang, J. Li, Y. Zhang, and N.A. Xu. 2011. Inactivation of TLR9 by a suppressive oligodeoxynucleotides can ameliorate the clinical signs of EAN. Immunological Investigations 41: 171–182.PubMedCrossRefGoogle Scholar
  15. 15.
    Bernasconi, P., M. Barberis, F. Baggi, L. Passerini, M. Cannone, E. Arnoldi, L. Novellino, F. Cornelio, and R. Mantegazza. 2005. Increased Toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution. The American Journal of Pathology 167: 129–139.PubMedCrossRefGoogle Scholar
  16. 16.
    Montero Vega, M.T., and A. de Andres Martin. 2008. Toll-like receptors: a family of innate sensors of danger that alert and drive immunity. Allergologia et Immunopathologia (Madr) 36: 347–357.CrossRefGoogle Scholar
  17. 17.
    Jaretzki 3rd, A., R.J. Barohn, R.M. Ernstoff, H.J. Kaminski, J.C. Keesey, A.S. Penn, and D.B. Sanders. 2000. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 55: 16–23.PubMedCrossRefGoogle Scholar
  18. 18.
    Osserman, K.E., and G. Genkins. 1971. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. The Mount Sinai Journal of Medicine 38: 497–537.Google Scholar
  19. 19.
    Sharshar, T., S. Chevret, M. Mazighi, P. Chillet, G. Huberfeld, C. Berreotta, M. Houfani, and P. Gajdos. 2000. Validity and reliability of two muscle strength scores commonly used as endpoints in assessing treatment of myasthenia gravis. Journal of Neurology 247: 286–290.PubMedCrossRefGoogle Scholar
  20. 20.
    Rozkova, D., R. Horvath, J. Bartunkova, and R. Spisek. 2006. Glucocorticoids severely impair differentiation and antigen presenting function of dendritic cells despite upregulation of Toll-like receptors. Clinical Immunology 120: 260–271.PubMedCrossRefGoogle Scholar
  21. 21.
    McCoy, C.E., S. Carpenter, E.M. Palsson-McDermott, L.J. Gearing, and L.A. O'Neill. 2008. Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation. The Journal of Biological Chemistry 283: 14277–14285.PubMedCrossRefGoogle Scholar
  22. 22.
    Roelofs, M.F., M.H. Wenink, F. Brentano, S. Abdollahi-Roodsaz, B. Oppers-Walgreen, P. Barrera, P.L. van Riel, L.A. Joosten, D. Kyburz, W.B. van den Berg, and T.R. Radstake. 2009. Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA). Annals of the Rheumatic Diseases 68: 1486–1493.PubMedCrossRefGoogle Scholar
  23. 23.
    Kessel, A., R. Peri, T. Haj, A. Snir, G. Slobodin, E. Sabo, I. Rosner, Y. Shoenfeld, and E. Toubi. 2011. IVIg attenuates TLR-9 activation in B cells from SLE patients. Journal of Clinical Immunology 31: 30–38.PubMedCrossRefGoogle Scholar
  24. 24.
    Marta, M., A. Andersson, M. Isaksson, O. Kampe, and A. Lobell. 2008. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. European Journal of Immunology 38: 565–575.PubMedCrossRefGoogle Scholar
  25. 25.
    Muzio, M., N. Polentarutti, D. Bosisio, P.P. Manoj Kumar, and A. Mantovani. 2000. Toll-like receptor family and signalling pathway. Biochemical Society Transactions 28: 563–566.PubMedGoogle Scholar
  26. 26.
    Chow, J.C., D.W. Young, D.T. Golenbock, W.J. Christ, and F. Gusovsky. 1999. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. The Journal of Biological Chemistry 274: 10689–10692.PubMedCrossRefGoogle Scholar
  27. 27.
    Lee, K.S., C.A. Scanga, E.M. Bachelder, Q. Chen, and C.M. Snapper. 2007. TLR2 synergizes with both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Streptococcus pneumoniae. Cellular Immunology 245: 103–110.PubMedCrossRefGoogle Scholar
  28. 28.
    Krieg, A.M. 2002. CpG motifs in bacterial DNA and their immune effects. Annual Review of Immunology 20: 709–760.PubMedCrossRefGoogle Scholar
  29. 29.
    Riccardi, C., S. Bruscoli, and G. Migliorati. 2002. Molecular mechanisms of immunomodulatory activity of glucocorticoids. Pharmacological Research 45: 361–368.PubMedCrossRefGoogle Scholar
  30. 30.
    Chinenov, Y., and I. Rogatsky. 2007. Glucocorticoids and the innate immune system: crosstalk with the Toll-like receptor signaling network. Molecular and Cellular Endocrinology 275: 30–42.PubMedCrossRefGoogle Scholar
  31. 31.
    Lepelletier, Y., R. Zollinger, C. Ghirelli, F. Raynaud, R. Hadj-Slimane, A. Cappuccio, O. Hermine, Y.J. Liu, and V. Soumelis. 2010. Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs). Blood 116: 3389–3397.PubMedCrossRefGoogle Scholar
  32. 32.
    Bhattacharyya, S., D.E. Brown, J.A. Brewer, S.K. Vogt, and L.J. Muglia. 2007. Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 109: 4313–4319.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yu-Zhong Wang
    • 1
    • 2
  • Mei Yan
    • 1
  • Fa-Fa Tian
    • 1
  • Jun-Mei Zhang
    • 1
  • Qun Liu
    • 1
  • Huan Yang
    • 1
  • Wen-Bin Zhou
    • 1
  • Jing Li
    • 1
  1. 1.Department of Neurology, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  2. 2.Department of NeurologyAffiliated Hospital of Jining Medical CollegeJiningPeople’s Republic of China

Personalised recommendations