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Review on Toll-Like Receptor Activation in Myasthenia Gravis: Application to the Development of New Experimental Models

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Abstract

Abnormal toll-like receptor (TLR) activation and uncontrolled resolution of inflammation are suspected to play a key role in the development of autoimmune diseases. Acquired myasthenia gravis (MG) is an invalidating neuromuscular disease leading to muscle weaknesses. MG is mainly mediated by anti-acetylcholine receptor (AChR) autoantibodies, and thymic hyperplasia characterized by ectopic germinal centers is a common feature in MG. An abnormal expression of certain TLRs is observed in the thymus of MG patients associated with the overexpression of interferon (IFN)-β, the orchestrator of thymic changes in MG. Experimental models have been developed for numerous autoimmune diseases. These models are induced by animal immunization with a purified antigen solubilized in complete Freund’s adjuvant (CFA) containing heat-inactivated mycobacterium tuberculosis (MTB). Sensitization against the antigen is mainly due to the activation of TLR signaling pathways by the pathogen motifs displayed by MTB, and attempts have been made to substitute the use of CFA by TLR agonists. AChR emulsified in CFA is used to induce the classical experimental autoimmune MG model (EAMG). However, the TLR4 activator lipopolysaccharide (LPS) has proved to be efficient to replace MTB and induce a sensitization against purified AChR. Poly(I:C), the well-known TLR3 agonist, is also able by itself to induce MG symptoms in mice associated with early thymic changes as observed in human MG. In this review, we discuss the abnormal expression of TLRs in MG patients and we describe the use of TLR agonists to induce EAMG in comparison with other autoimmune experimental models.

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Abbreviations

AChR:

Acetylcholine receptor

CFA:

Complete Freund’s adjuvant

EAMG:

Experimental autoimmune myasthenia gravis

EBV:

Epstein-Barr virus

EOMG:

Early-onset MG

GC:

Germinal center

IFA:

Incomplete Freund’s adjuvant

IFN:

Interferon

IL:

Interleukin

IRF:

IFN-regulatory factor

KO:

Knock-out

MG:

Myasthenia gravis

MyD88:

Myeloid differentiation primary response gene 88

PBMCs:

Peripheral blood mononuclear cells

Poly(I:C):

Polyinosinic-polycytidylic acid

TEC:

Thymic epithelial cell

TLR:

Toll-like receptor

TRIF:

TIR domain-containing adapter-inducing interferon-β

References

  1. Berrih-Aknin S, Le Panse R (2014) Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun 52:90–100

    Article  CAS  PubMed  Google Scholar 

  2. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A et al (2001) Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7:365–368

    Article  CAS  PubMed  Google Scholar 

  3. Higuchi O, Hamuro J, Motomura M, Yamanashi Y (2011) Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 69:418–422

    Article  CAS  PubMed  Google Scholar 

  4. Zhang B, Shen C, Bealmear B, Ragheb S, Xiong WC et al (2014) Autoantibodies to agrin in myasthenia gravis patients. PLoS One 9, e91816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Nicolle MW (2002) Myasthenia gravis. Neurologist 8:2–21

    Article  PubMed  Google Scholar 

  6. Berrih-Aknin S, Morel E, Raimond F, Safar D, Gaud C et al (1987) The role of the thymus in myasthenia gravis: immunohistological and immunological studies in 115 cases. Ann N Y Acad Sci 505:50–70

    Article  CAS  PubMed  Google Scholar 

  7. Levinson AI, Wheatley LM (1996) The thymus and the pathogenesis of myasthenia gravis. Clin Immunol Immunopathol 78:1–5

    Article  CAS  PubMed  Google Scholar 

  8. Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F et al (2003) Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 126:2304–2311

    Article  PubMed  Google Scholar 

  9. Ponseti JM, Caritg N, Gamez J, Lopez-Cano M, Vilallonga R et al (2009) A comparison of long-term post-thymectomy outcome of anti-AChR-positive, anti-AChR-negative and anti-MuSK-positive patients with non-thymomatous myasthenia gravis. Expert Opin Biol Ther 9:1–8

    Article  CAS  PubMed  Google Scholar 

  10. Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33:256–263

    Article  CAS  PubMed  Google Scholar 

  11. Suniara RK, Jenkinson EJ, Owen JJ (2000) An essential role for thymic mesenchyme in early T cell development. J Exp Med 191:1051–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S et al (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202:33–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Berrih-Aknin S, Ruhlmann N, Bismuth J, Cizeron-Clairac G, Zelman E et al (2009) CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia. Ann Neurol 66:521–531

    Article  CAS  PubMed  Google Scholar 

  14. Le Panse R, Bismuth J, Cizeron-Clairac G, Weiss JM, Cufi P et al (2010) Thymic remodeling associated with hyperplasia in myasthenia gravis. Autoimmunity 43:1–12

    Article  Google Scholar 

  15. Weiss JM, Cufi P, Bismuth J, Eymard B, Fadel E et al (2013) SDF-1/CXCL12 recruits B cells and antigen-presenting cells to the thymus of autoimmune myasthenia gravis patients. Immunobiology 218:373–381

    Article  CAS  PubMed  Google Scholar 

  16. Weiss JM, Cufi P, Le Panse R, Berrih-Aknin S (2013) The thymus in autoimmune myasthenia gravis: paradigm for a tertiary lymphoid organ. Rev Neurol (Paris) 169:640–649

    Article  Google Scholar 

  17. Ruddle NH (2014) Lymphatic vessels and tertiary lymphoid organs. J Clin Invest 124:953–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wakkach A, Guyon T, Bruand C, Tzartos S, Cohen-Kaminsky S et al (1996) Expression of acetylcholine receptor genes in human thymic epithelial cells: implications for myasthenia gravis. J Immunol 157:3752–3760

    CAS  PubMed  Google Scholar 

  19. Safar D, Berrih-Aknin S, Morel E (1987) In vitro anti-acetylcholine receptor antibody synthesis by myasthenia gravis patient lymphocytes: correlations with thymic histology and thymic epithelial-cell interactions. J Clin Immunol 7:225–234

    Article  CAS  PubMed  Google Scholar 

  20. Leprince C, Cohen-Kaminsky S, Berrih-Aknin S, Vernet-Der Garabedian B, Treton D et al (1990) Thymic B cells from myasthenia gravis patients are activated B cells phenotypic and functional analysis. J Immunol 145:2115–2122

    CAS  PubMed  Google Scholar 

  21. Melms A, Schalke BC, Kirchner T, Muller-Hermelink HK, Albert E et al (1988) Thymus in myasthenia gravis. Isolation of T-lymphocyte lines specific for the nicotinic acetylcholine receptor from thymuses of myasthenic patients. J Clin Invest 81:902–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kuks JB, Oosterhuis HJ, Limburg PC, The TH (1991) Anti-acetylcholine receptor antibodies decrease after thymectomy in patients with myasthenia gravis clinical correlations. J Autoimmun 4:197–211

    Article  CAS  PubMed  Google Scholar 

  23. Papatestas AE, Alpert LI, Osserman KE, Osserman RS, Kark AE (1971) Studies in myasthenia gravis: effects of thymectomy. Results on 185 patients with nonthymomatous and thymomatous myasthenia gravis, 1941–1969. Am J Med 50:465–474

    Article  CAS  PubMed  Google Scholar 

  24. Feferman T, Maiti PK, Berrih-Aknin S, Bismuth J, Bidault J et al (2005) Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis. J Immunol 174:5324–5331

    Article  CAS  PubMed  Google Scholar 

  25. Cordiglieri C, Marolda R, Franzi S, Cappelletti C, Giardina C et al (2014) Innate immunity in myasthenia gravis thymus: pathogenic effects of Toll-like receptor 4 signaling on autoimmunity. J Autoimmun 52:74–89

    Article  CAS  PubMed  Google Scholar 

  26. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M et al (1998) B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med 187:655–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Barone F, Bombardieri M, Manzo A, Blades MC, Morgan PR et al (2005) Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren’s syndrome. Arthritis Rheum 52:1773–1784

    Article  CAS  PubMed  Google Scholar 

  28. Méraouna A, Cizeron-Clairac G, Le Panse R, Bismuth J, Truffault F et al (2006) The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. Blood 108:432–440

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Le Panse R, Cizeron-Clairac G, Bismuth J, Berrih-Aknin S (2006) Microarrays reveal distinct gene signatures in the thymus of seropositive and seronegative myasthenia gravis patients and the role of CC chemokine ligand 21 in thymic hyperplasia. J Immunol 177:7868–7879

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shiao YM, Lee CC, Hsu YH, Huang SF, Lin CY et al (2010) Ectopic and high CXCL13 chemokine expression in myasthenia gravis with thymic lymphoid hyperplasia. J Neuroimmunol 221:101–106

    Article  CAS  PubMed  Google Scholar 

  31. Zhang M, Guo J, Li H, Zhou Y, Tian F et al (2013) Expression of immune molecules CD25 and CXCL13 correlated with clinical severity of myasthenia gravis. J Mol Neurosci 50:317–323

    Article  CAS  PubMed  Google Scholar 

  32. Stubgen JP (2009) Interferon alpha and neuromuscular disorders. J Neuroimmunol 207:3–17

    Article  PubMed  CAS  Google Scholar 

  33. Meager A, Wadhwa M, Dilger P, Bird C, Thorpe R et al (2003) Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis. Clin Exp Immunol 132:128–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Meloni A, Furcas M, Cetani F, Marcocci C, Falorni A et al (2008) Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 93:4389–4397

    Article  CAS  PubMed  Google Scholar 

  35. Poea-Guyon S, Christadoss P, Le Panse R, Guyon T, De Baets M et al (2005) Effects of cytokines on acetylcholine receptor expression: implications for myasthenia gravis. J Immunol 174:5941–5949

    Article  CAS  PubMed  Google Scholar 

  36. Le Panse R, Cizeron-Clairac G, Cuvelier M, Truffault F, Bismuth J et al (2008) Regulatory and pathogenic mechanisms in human autoimmune myasthenia gravis. Ann N Y Acad Sci 1132:135–142

    Article  PubMed  CAS  Google Scholar 

  37. Golding A, Rosen A, Petri M, Akhter E, Andrade F (2010) Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses. Immunology 131:107–117

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Cufi P, Dragin N, Weiss JM, Martinez-Martinez P, De Baets MH et al (2013) Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis. Ann Neurol 73:281–293

    Article  CAS  PubMed  Google Scholar 

  39. Cufi P, Dragin N, Ruhlmann N, Weiss JM, Fadel E et al (2014) Central role of interferon-beta in thymic events leading to myasthenia gravis. J Autoimmun 52:44–52

    Article  CAS  PubMed  Google Scholar 

  40. Weiss JM, Robinet M, Aricha R, Cufi P, Villeret B et al (2016) Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis., Oncotarget

  41. Cufi P, Soussan P, Truffault F, Fetouchi R, Robinet M et al (2014) Thymoma-associated myasthenia gravis: on the search for a pathogen signature. J Autoimmun 52:29–35

    Article  CAS  PubMed  Google Scholar 

  42. Okada H, Kuhn C, Feillet H, Bach JF (2010) The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol 160:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Munz C, Lunemann JD, Getts MT, Miller SD (2009) Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol 9:246–258

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Savino W (2006) The thymus is a common target organ in infectious diseases. PLoS Pathog 2, e62

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Cavalcante P, Barberis M, Cannone M, Baggi F, Antozzi C et al (2010) Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis. Neurology 74:1118–1126

    Article  CAS  PubMed  Google Scholar 

  46. Cavalcante P, Serafini B, Rosicarelli B, Maggi L, Barberis M et al (2010) Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol 67:726–738

    PubMed  Google Scholar 

  47. Niller HH, Wolf H, Ay E, Minarovits J (2011) Epigenetic dysregulation of Epstein-Barr virus latency and development of autoimmune disease. Adv Exp Med Biol 711:82–102

    Article  CAS  PubMed  Google Scholar 

  48. Ning S (2011) Innate immune modulation in EBV infection. Herpesviridae 2:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  PubMed  Google Scholar 

  50. Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Mohammad Hosseini A, Majidi J, Baradaran B, Yousefi M (2015) Toll-like receptors in the pathogenesis of autoimmune diseases. Adv Pharm Bull 5:605–614

    Article  PubMed  PubMed Central  Google Scholar 

  52. Chen JQ, Szodoray P, Zeher M (2016) Toll-like receptor pathways in autoimmune diseases. Clin Rev Allergy Immunol 50:1–17

    Article  CAS  PubMed  Google Scholar 

  53. Choi YJ, Im E, Chung HK, Pothoulakis C, Rhee SH (2010) TRIF mediates toll-like receptor 5-induced signaling in intestinal epithelial cells. J Biol Chem 285:37570–37578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Volpi C, Fallarino F, Pallotta MT, Bianchi R, Vacca C et al (2013) High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TRIF pathway. Nat Commun 4:1852

    Article  PubMed  CAS  Google Scholar 

  55. Nilsen NJ, Vladimer GI, Stenvik J, Orning MP, Zeid-Kilani MV et al (2015) A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling. J Biol Chem 290:3209–3222

    Article  CAS  PubMed  Google Scholar 

  56. Perkins DJ, Vogel SN (2015) Space and time: new considerations about the relationship between toll-like receptors (TLRs) and type I interferons (IFNs). Cytokine 74:171–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pohar J, Pirher N, Bencina M, Mancek-Keber M, Jerala R (2013) The role of UNC93B1 protein in surface localization of TLR3 receptor and in cell priming to nucleic acid agonists. J Biol Chem 288:442–454

    Article  CAS  PubMed  Google Scholar 

  58. Kanno A, Tanimura N, Ishizaki M, Ohko K, Motoi Y et al (2015) Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases. Nat Commun 6:6119

    Article  CAS  PubMed  Google Scholar 

  59. Itoh H, Tatematsu M, Watanabe A, Iwano K, Funami K et al (2011) UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling. PLoS One 6, e28500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Guerrier T, Pochard P, Lahiri A, Youinou P, Pers JO et al (2014) TLR9 expressed on plasma membrane acts as a negative regulator of human B cell response. J Autoimmun 51:23–29

    Article  CAS  PubMed  Google Scholar 

  61. Hurst J, von Landenberg P (2008) Toll-like receptors and autoimmunity. Autoimmun Rev 7:204–208

    Article  CAS  PubMed  Google Scholar 

  62. Duthie MS, Windish HP, Fox CB, Reed SG (2011) Use of defined TLR ligands as adjuvants within human vaccines. Immunol Rev 239:178–196

    Article  CAS  PubMed  Google Scholar 

  63. Jin B, Sun T, Yu XH, Yang YX, Yeo AE (2012) The effects of TLR activation on T-cell development and differentiation. Clin Dev Immunol 2012:836485

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Crampton SP, Voynova E, Bolland S (2010) Innate pathways to B-cell activation and tolerance. Ann N Y Acad Sci 1183:58–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Green NM, Moody KS, Debatis M, Marshak-Rothstein A (2012) Activation of autoreactive B cells by endogenous TLR7 and TLR3 RNA ligands., J Biol Chem

  66. Meyer-Bahlburg A, Rawlings DJ (2008) B cell autonomous TLR signaling and autoimmunity. Autoimmun Rev 7:313–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Green NM, Marshak-Rothstein A (2011) Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. Semin Immunol 23:106–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang YZ, Yan M, Tian FF, Zhang JM, Liu Q et al (2013) Possible involvement of toll-like receptors in the pathogenesis of myasthenia gravis. Inflammation 36:121–130

    Article  CAS  PubMed  Google Scholar 

  69. Lu J, Yan M, Wang Y, Zhang J, Yang H et al (2013) Altered expression of miR-146a in myasthenia gravis. Neurosci Lett 555:85–90

    Article  CAS  PubMed  Google Scholar 

  70. Zarember KA, Godowski PJ (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. J Immunol 168:554–561

    Article  CAS  PubMed  Google Scholar 

  71. Bernasconi P, Barberis M, Baggi F, Passerini L, Cannone M et al (2005) Increased toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution. Am J Pathol 167:129–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cavalcante P, Galbardi B, Franzi S, Marcuzzo S, Barzago C et al (2016) Increased expression of toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein-Barr virus infection. Immunobiology 221:516–527

    Article  CAS  PubMed  Google Scholar 

  73. Quan TE, Roman RM, Rudenga BJ, Holers VM, Craft JE (2010) Epstein-Barr virus promotes interferon-alpha production by plasmacytoid dendritic cells. Arthritis Rheum 62:1693–1701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Iwakiri D, Zhou L, Samanta M, Matsumoto M, Ebihara T et al (2009) Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3. J Exp Med 206:2091–2099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gaudreault E, Fiola S, Olivier M, Gosselin J (2007) Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J Virol 81:8016–8024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Valente RM, Ehlers E, Xu D, Ahmad H, Steadman A et al (2012) Toll-like receptor 7 stimulates the expression of Epstein-Barr virus latent membrane protein 1. PLoS One 7, e43317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Fuchs S, Aricha R, Reuveni D, Souroujon MC (2014) Experimental autoimmune myasthenia gravis (EAMG): from immunochemical characterization to therapeutic approaches. J Autoimmun 54:51–59

    Article  CAS  PubMed  Google Scholar 

  78. Tuzun E, Berrih-Aknin S, Brenner T, Kusner LL, Le Panse R et al (2015) Guidelines for standard preclinical experiments in the mouse model of myasthenia gravis induced by acetylcholine receptor immunization., Exp Neurol

  79. Wu B, Goluszko E, Huda R, Tuzun E, Christadoss P (2013) Experimental autoimmune myasthenia gravis in the mouse. Curr Protoc Immunol Chapter 15: Unit 15 18.

  80. Losen M, Martinez-Martinez P, Molenaar PC, Lazaridis K, Tzartos S et al (2015) Standardization of the experimental autoimmune myasthenia gravis (EAMG) model by immunization of rats with Torpedo californica acetylcholine receptors—recommendations for methods and experimental designs. Exp Neurol 270:18–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Billiau A, Matthys P (2001) Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J Leukoc Biol 70:849–860

    CAS  PubMed  Google Scholar 

  82. Milani M, Ostlie N, Wu H, Wang W, Conti-Fine BM (2006) CD4+ T and B cells cooperate in the immunoregulation of experimental autoimmune myasthenia gravis. J Neuroimmunol 179:152–162

    Article  CAS  PubMed  Google Scholar 

  83. Shibaki A, Katz SI (2002) Induction of skewed Th1/Th2 T-cell differentiation via subcutaneous immunization with Freund’s adjuvant. Exp Dermatol 11:126–134

    Article  CAS  PubMed  Google Scholar 

  84. Balasa B, Deng C, Lee J, Bradley LM, Dalton DK et al (1997) Interferon gamma (IFN-gamma) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J Exp Med 186:385–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang GX, Xiao BG, Bai XF, van der Meide PH, Orn A et al (1999) Mice with IFN-gamma receptor deficiency are less susceptible to experimental autoimmune myasthenia gravis. J Immunol 162:3775–3781

    CAS  PubMed  Google Scholar 

  86. Schaffert H, Pelz A, Saxena A, Losen M, Meisel A et al (2015) IL-17-producing CD4(+) T cells contribute to the loss of B-cell tolerance in experimental autoimmune myasthenia gravis. Eur J Immunol 45:1339–1347

    Article  CAS  PubMed  Google Scholar 

  87. Gavin AL, Hoebe K, Duong B, Ota T, Martin C et al (2006) Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314:1936–1938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Su SB, Silver PB, Grajewski RS, Agarwal RK, Tang J et al (2005) Essential role of the MyD88 pathway, but nonessential roles of TLRs 2, 4, and 9, in the adjuvant effect promoting Th1-mediated autoimmunity. J Immunol 175:6303–6310

    Article  CAS  PubMed  Google Scholar 

  89. Marty RR, Dirnhofer S, Mauermann N, Schweikert S, Akira S et al (2006) MyD88 signaling controls autoimmune myocarditis induction. Circulation 113:258–265

    Article  CAS  PubMed  Google Scholar 

  90. Sadanaga A, Nakashima H, Akahoshi M, Masutani K, Miyake K et al (2007) Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice. Arthritis Rheum 56:1618–1628

    Article  CAS  PubMed  Google Scholar 

  91. Fang J, Fang D, Silver PB, Wen F, Li B et al (2010) The role of TLR2, TRL3, TRL4, and TRL9 signaling in the pathogenesis of autoimmune disease in a retinal autoimmunity model. Invest Ophthalmol Vis Sci 51:3092–3099

    Article  PubMed  PubMed Central  Google Scholar 

  92. Scadding GK, Calder L, Vincent A, Prior C, Wray D et al (1986) Anti-acetylcholine receptor antibodies induced in mice by syngeneic receptor without adjuvants. Immunology 58:151–155

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jermy A, Beeson D, Vincent A (1993) Pathogenic autoimmunity to affinity-purified mouse acetylcholine receptor induced without adjuvant in BALB/c mice. Eur J Immunol 23:973–976

    Article  CAS  PubMed  Google Scholar 

  94. Kool M, Soullie T, van Nimwegen M, Willart MA, Muskens F et al (2008) Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med 205:869–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Oshima M, Maruta T, Ohtani M, Deitiker PR, Mosier D et al (2006) Vaccination with a MHC class II peptide in alum and inactive pertussis strongly ameliorates clinical MG in C57BL/6 mice. J Neuroimmunol 171:8–16

    Article  CAS  PubMed  Google Scholar 

  96. Bennett B, Check IJ, Olsen MR, Hunter RL (1992) A comparison of commercially available adjuvants for use in research. J Immunol Methods 153:31–40

    Article  CAS  PubMed  Google Scholar 

  97. Shenoy M, Christadoss P (1993) Induction of experimental autoimmune myasthenia gravis with acetylcholine receptors using a nonionic block copolymer as adjuvant. Immunol Investig 22:267–282

    Article  CAS  Google Scholar 

  98. Lu YC, Yeh WC, Ohashi PS (2008) LPS/TLR4 signal transduction pathway. Cytokine 42:145–151

    Article  CAS  PubMed  Google Scholar 

  99. Demon D, Vande Walle L, Lamkanfi M (2014) Sensing the enemy within: how macrophages detect intracellular Gram-negative bacteria. Trends Biochem Sci 39:574–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Liu Y, Yin H, Zhao M, Lu Q (2014) TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol 47:136–147

    Article  CAS  PubMed  Google Scholar 

  101. Allman W, Qi H, Saini SS, Li J, Tuzun E et al (2012) CD4 costimulation is not required in a novel LPS-enhanced model of myasthenia gravis. J Neuroimmunol 249:1–7

  102. Rose NR (2008) The adjuvant effect in infection and autoimmunity. Clin Rev Allergy Immunol 34:279–282

    Article  CAS  PubMed  Google Scholar 

  103. Damotte D, Goulvestre C, Charreire J, Carnaud C (2003) LPS and Freund’s adjuvant initiate different inflammatory circuits in experimental autoimmune thyroiditis. Eur Cytokine Netw 14:52–59

    CAS  PubMed  Google Scholar 

  104. Deane JA, Bolland S (2006) Nucleic acid-sensing TLRs as modifiers of autoimmunity. J Immunol 177:6573–6578

    Article  CAS  PubMed  Google Scholar 

  105. Berman PW, Patrick J (1980) Experimental myasthenia gravis. A murine system. J Exp Med 151:204–223

    Article  CAS  PubMed  Google Scholar 

  106. Fujii Y, Monden Y, Hashimoto J, Nakahara K, Kawashima Y (1985) Acetylcholine receptor antibody-producing cells in thymus and lymph nodes in myasthenia gravis. Clin Immunol Immunopathol 34:141–146

    Article  CAS  PubMed  Google Scholar 

  107. Zare F, Bokarewa M, Nenonen N, Bergstrom T, Alexopoulou L et al (2004) Arthritogenic properties of double-stranded (viral) RNA. J Immunol 172:5656–5663

    Article  CAS  PubMed  Google Scholar 

  108. Okada C, Akbar SM, Horiike N, Onji M (2005) Early development of primary biliary cirrhosis in female C57BL/6 mice because of poly I:C administration. Liver Int 25:595–603

    Article  CAS  PubMed  Google Scholar 

  109. Asada M, Nishio A, Akamatsu T, Tanaka J, Saga K et al (2010) Analysis of humoral immune response in experimental autoimmune pancreatitis in mice. Pancreas 39:224–231

    Article  CAS  PubMed  Google Scholar 

  110. Patole PS, Grone HJ, Segerer S, Ciubar R, Belemezova E et al (2005) Viral double-stranded RNA aggravates lupus nephritis through toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells. J Am Soc Nephrol 16:1326–1338

    Article  CAS  PubMed  Google Scholar 

  111. Jorgensen TN, Thurman J, Izui S, Falta MT, Metzger TE et al (2006) Genetic susceptibility to polyI:C-induced IFNalpha/beta-dependent accelerated disease in lupus-prone mice. Genes Immun 7:555–567

    Article  CAS  PubMed  Google Scholar 

  112. Nandula SR, Scindia YM, Dey P, Bagavant H, Deshmukh US (2011) Activation of innate immunity accelerates sialoadenitis in a mouse model for Sjogren’s syndrome-like disease. Oral Dis 17:801–807

    Article  PubMed  PubMed Central  Google Scholar 

  113. Moriyama H, Wen L, Abiru N, Liu E, Yu L et al (2002) Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. Proc Natl Acad Sci U S A 99:5539–5544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ren X, Zhou H, Li B, Su SB (2011) Toll-like receptor 3 ligand polyinosinic:polycytidylic acid enhances autoimmune disease in a retinal autoimmunity model. Int Immunopharmacol 11:769–773

    Article  CAS  PubMed  Google Scholar 

  115. Ambrosini YM, Yang GX, Zhang W, Tsuda M, Shu S et al (2011) The multi-hit hypothesis of primary biliary cirrhosis: polyinosinic-polycytidylic acid (poly I:C) and murine autoimmune cholangitis. Clin Exp Immunol 166:110–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Touil T, Fitzgerald D, Zhang GX, Rostami A, Gran B (2006) Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J Immunol 177:7505–7509

    Article  CAS  PubMed  Google Scholar 

  117. Khorooshi R, Morch MT, Holm TH, Berg CT, Dieu RT et al (2015) Induction of endogenous type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis. Acta Neuropathol 130:107–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jankovic SM (2010) Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis. J Inflamm Res 3:25–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lennon VA, Lindstrom JM, Seybold ME (1975) Experimental autoimmune myasthenia: a model of myasthenia gravis in rats and guinea pigs. J Exp Med 141:1365–1375

    Article  CAS  PubMed  Google Scholar 

  120. Fuchs S, Nevo D, Tarrab-Hazdai R, Yaar I (1976) Strain differences in the autoimmune response of mice to acetylcholine receptors. Nature 263:329–330

    Article  CAS  PubMed  Google Scholar 

  121. Meinl E, Klinkert WE, Wekerle H (1991) The thymus in myasthenia gravis. Changes typical for the human disease are absent in experimental autoimmune myasthenia gravis of the Lewis rat. Am J Pathol 139:995–1008

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Lennon VA, Lindstrom JM, Seybold ME (1976) Experimental autoimmune myasthenia gravis: cellular and humoral immune responses. Ann N Y Acad Sci 274:283–299

    Article  CAS  PubMed  Google Scholar 

  123. Fallarino F, Volpi C, Zelante T, Vacca C, Calvitti M et al (2009) IDO mediates TLR9-driven protection from experimental autoimmune diabetes. J Immunol 183:6303–6312

    Article  CAS  PubMed  Google Scholar 

  124. Gilboa-Geffen A, Wolf Y, Hanin G, Melamed-Book N, Pick M et al (2011) Activation of the alternative NFkappaB pathway improves disease symptoms in a model of Sjogren’s syndrome. PLoS One 6, e28727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Longhini AL, Santos MP, Pradella F, Moraes AS, Dionete AC et al (2014) In vivo administration of TLR9 agonist reduces the severity of experimental autoimmune encephalomyelitis. The role of plasmacytoid dendritic cells and B lymphocytes. CNS Neurosci Ther 20:787–790

    Article  CAS  PubMed  Google Scholar 

  126. Farhat K, Riekenberg S, Heine H, Debarry J, Lang R et al (2008) Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. J Leukoc Biol 83:692–701

    Article  CAS  PubMed  Google Scholar 

  127. van Bergenhenegouwen J, Plantinga TS, Joosten LA, Netea MG, Folkerts G et al (2013) TLR2 & Co: a critical analysis of the complex interactions between TLR2 and coreceptors. J Leukoc Biol 94:885–902

    Article  PubMed  CAS  Google Scholar 

  128. Nishiya T, Kajita E, Miwa S, Defranco AL (2005) TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J Biol Chem 280:37107–37117

    Article  CAS  PubMed  Google Scholar 

  129. Tatematsu M, Seya T, Matsumoto M (2014) Beyond dsRNA: toll-like receptor 3 signalling in RNA-induced immune responses. Biochem J 458:195–201

    Article  CAS  PubMed  Google Scholar 

  130. Liaunardy-Jopeace A, Gay NJ (2014) Molecular and cellular regulation of toll-like receptor-4 activity induced by lipopolysaccharide ligands. Front Immunol 5:473

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Miao EA, Andersen-Nissen E, Warren SE, Aderem A (2007) TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol 29:275–288

    Article  CAS  PubMed  Google Scholar 

  132. Guiducci C, Gong M, Cepika AM, Xu Z, Tripodo C et al (2013) RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp Med 210:2903–2919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Huang X, Yang Y (2010) Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses. Expert Opin Ther Targets 14:787–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E et al (2005) Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 174:2942–2950

    Article  CAS  PubMed  Google Scholar 

  135. Lee SM, Kok KH, Jaume M, Cheung TK, Yip TF et al (2014) Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection. Proc Natl Acad Sci U S A 111:3793–3798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hatai H, Lepelley A, Zeng W, Hayden MS, Ghosh S (2016) Toll-like receptor 11 (TLR11) interacts with flagellin and profilin through disparate mechanisms. PLoS One 11, e0148987

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Cho YG, Cho ML, Min SY, Kim HY (2007) Type II collagen autoimmunity in a mouse model of human rheumatoid arthritis. Autoimmun Rev 7:65–70

    Article  CAS  PubMed  Google Scholar 

  138. Libbey JE, Fujinami RS (2011) Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. Vaccine 29:3356–3362

    Article  CAS  PubMed  Google Scholar 

  139. Allenbach Y, Solly S, Gregoire S, Dubourg O, Salomon B et al (2009) Role of regulatory T cells in a new mouse model of experimental autoimmune myositis. Am J Pathol 174:989–998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lohse AW, Manns M, Dienes HP, Buschenfelde KH M z, Cohen IR (1990) Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity. Hepatology 11:24–30

    Article  CAS  PubMed  Google Scholar 

  141. Jones DE, Palmer JM, Kirby JA, De Cruz DJ, McCaughan GW et al (2000) Experimental autoimmune cholangitis: a mouse model of immune-mediated cholangiopathy. Liver 20:351–356

    Article  CAS  PubMed  Google Scholar 

  142. Little MA, Smyth L, Salama AD, Mukherjee S, Smith J et al (2009) Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis. Am J Pathol 174:1212–1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Tincani A, Gilburd B, Abu-Shakra M, Blank M, Allegri F et al (2002) Immunization of naive BALB/c mice with human beta2-glycoprotein I breaks tolerance to the murine molecule. Arthritis Rheum 46:1399–1404

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Profs Remi Nottin and Elie Fadel for the thymic samples and Vincent de Montpreville for the histological analyses. We thank the “Agence Nationale de la Recherche” (ANR-06-MRAR-001-01) from the European Community (MYASTAID/LSHM-CT-2006-037833 and FIGHT-MG/HEALTH-2009-242-210) and from the “Association Française contre les Myopathies” (AFM).

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Authors and Affiliations

  1. INSERM U974, Paris, France

    Marieke Robinet, Solène Maillard, Mélanie A. Cron, Sonia Berrih-Aknin & Rozen Le Panse

  2. CNRS FRE3617, Paris, France

    Marieke Robinet, Solène Maillard, Mélanie A. Cron, Sonia Berrih-Aknin & Rozen Le Panse

  3. Sorbonne Universités, UPMC University Paris 06, Paris, France

    Marieke Robinet, Solène Maillard, Mélanie A. Cron, Sonia Berrih-Aknin & Rozen Le Panse

  4. AIM, Institut de Myologie, Paris, France

    Marieke Robinet, Solène Maillard, Mélanie A. Cron, Sonia Berrih-Aknin & Rozen Le Panse

  5. UMRS 974 UPMC, INSERM, FRE 3617 CNRS, AIM, Center of Research in Myology, 105 Boulevard de l’Hôpital, 75013, Paris, France

    Rozen Le Panse

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  1. Marieke Robinet
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Robinet, M., Maillard, S., Cron, M.A. et al. Review on Toll-Like Receptor Activation in Myasthenia Gravis: Application to the Development of New Experimental Models. Clinic Rev Allerg Immunol 52, 133–147 (2017). https://doi.org/10.1007/s12016-016-8549-4

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