The Current View of Immunopathogenesis of Myasthenia Gravis
Authors:
M. Jakubíková 1; J. Piťha 1,2
Authors place of work:
Neurologická klinika a Centrum klinických neurověd, 1. LF UK a VFN v Praze
1; MS Centrum Teplice, Neurologické oddělení, Krajská zdravotní, a. s. – Nemocnice Teplice o. z.
2
Published in the journal:
Cesk Slov Neurol N 2015; 78/111(6): 649-654
Category:
Review Article
Summary
Myasthenia gravis (MG) is an autoimmune disease that results in failure of neuromuscular transmission. Earlier theories of the dominant role of pathologic autoantibodies against target antigens (nicotinic acetylcholine receptor, muscle-specific tyrosine kinase and low-density lipoprotein receptor) were corrected following discovery of immune dysregulation at the level of T cells – between Th1 and Th2 and/or between T regulatory cells and Th17 cells, proliferation of CD8+ lymphocytes, chemokines, cytokines and other molecules. The immune system dysfunction can occur at different levels of the immune response: helper CD4+ T cells, cytotoxic CD8+ T cells, regulatory CD4+CD25+ T lymphocytes, Th17 lymphocytes, B lymphocytes and plasma cells. Thymus plays a dominant immunopathogenetic role in younger patients with MG, while extrathymic mechanisms are applied in older patients. Different immunologic mechanisms play a role in MG associated with a thymoma.
Key words:
myasthenia gravis – thymus – autoantibodies – T lymphocytes – B lymphocytes – cytokines
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Zdroje
1. Berrih‑ Aknin S, Le Panse R. Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun 2014; 52: 90– 100. doi: 10.1016/ j.jaut.2013.12.011.
2. Marx A, Wilisch A, Schultz A, Gattenlöhner S, Nenninger R, Müller‑ Hermelink HK. Pathogenesis of myasthenia gravis. Virchows Arch 1997; 430(5): 355– 364.
3. Kaminski HJ, Ruff RL. Structure and kinetic properties of the acetylcholine receptor. In: Engel AG (ed.) Myasthenia gravis and myasthenic disorders. Oxford: University Press 1999: 40– 64.
4. Kuks JBM. The thymus and myasthenia gravis. Doctoral thesis. Groningen: University of Groningen 1992.
5. Emilie D, Crevon MC, Cohen‑ Kaminski S, Peuchmaur M, Devergne O, Berrih‑ Aknin S et al. In situ production of interleukins in hyperplastic thymus from myasthenia gravis patients. Hum Pathol 1991; 22(5): 461– 468.
6. Lauriola L, Ranelletti F, Maggiano N, Guerriero M, Punzi C, Marsili F et al. Thymus changes in anti‑MUSK‑ positive and - negative myasthenia gravis. Neurology 2005; 64(3): 536– 538.
7. Špalek P. Myastenia gravis – autoimunitné spektrum a imunopatogenetická klasifikácia. Neurologia 2009; 4: 25– 30.
8. Ströbel P, Chuang WY, Marx A. Thymoma‑associated paraneoplastic myasthenia gravis. In: Kaminski HJ (ed.). Myasthenia gravis and related disorders. New York: Humana Press 2009: 105– 117.
9. Špalek P, Schnorrer M, Krajč T. Imunopatogenéza paraneoplastickej myastenie gravis asociovanej s tymómom. Neurologia 2010; 5: 7– 11.
10. Ströbel P, Helmreich M, Menioudakis G, Lewin SR, Rüdiger T, Bauer A et al. Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood 2002; 100(1): 159– 166.
11. Marx A, Hohenberger P, Pfannschmidt J, Wiebe K, Willcox N, Stro P. The autoimmune regulator AIRE in thy-moma biology: autoimmunity and beyond. J ThoracOncol 2010; 5 (Suppl 4): S266– S272. doi: 10.1097/ JTO.0b013e3181f1f63f.
12. Motomura M, Narita Masuda T. Autoantibodies in myasthenia gravis. Brain Nerve 2013; 65(4): 433– 439.
13. Engel AG, Fumagalli G. Mechanisms of acetylcholine receptor loss from the neuromuscular junction. Ciba Found Symp 1982; 90: 197– 224.
14. Dau PC. Plasmapheresis therapy in myasthenia gravis. Muscle Nerve 1980; 3(6): 468– 482.
15. Limburg PC, The TH, Hummel‑ Tappel E, Oosterhuis HJ. Anti‑acetylcholine receptor antibodies in myasthenia gravis. Part 1. Relation to clinical parameters in 250 patients. J Neurol Sci 1983; 58(3): 357– 370.
16. Špalek P. Tymómy a paraneoplastická autoimunita. Cesk Slov Neurol N 2002; 65/ 98(3): 367– 373.
17. Seybold ME, Lindstrom JM. Patterns of acetylcholine receptor antibody in myasthenia gravis. Ann N Y Acad Sci 1981; 377: 292– 306.
18. Conti‑Fine BM, Diethelm‑ Okita B, Ostlie N. Imunopathogenesis of myasthenia gravis. In: Kaminski HJ (ed.). Myasthenia gravis and related disorders. New York, Humana Press 2009: 43– 70.
19. Hoch W, McConville J, Helms S, Newsom‑ Davis J, Melms A, Vincent A. Autoantibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001; 7(3): 365– 368.
20. Weatherbee SD, Anderson KV, Niswander LA. LDL‑receptor‑related protein 4 is crucial for formation of the neuromuscular junction. Development 2006; 133(24): 4993– 5000.
21. Pevzner A, Schoser B, Peters K, Cosma NC, Karakatsani A, Schalke B et al. Anti‑LRP4 autoantibodies in AChR‑ and MuSK‑ antibody‑ negative myasthenia gravis. J Neurol 2012; 259(3): 427– 435. doi: 10.1007/ s00415‑ 011‑ 6194‑ 7.
22. Gomez AM, Burden SJ. The extracellular region of Lrp4 is sufficient to mediate neuromuscular synapse formation. Dev Dyn 2011; 240(12): 2626– 2633. doi: 10.1002/ dvdy.22772.
23. Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L. LRP4 Serves as a coreceptor of agrin. Neuron 2008; 60(2): 285– 297. doi: 10.1016/ j.neuron.2008.10.006.
24. Zisimopoulou P, Evangelakou P, Tzartos J, Lazaridis K, Zouvelou V, Mantegazza R et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti‑LRP4 in myasthenia gravis. J Autoimmun 2014; 52: 139– 145. doi: 10.1016/ j.jaut.2013.12.004.
25. Romi F, Skeie GO, Gilhus NE, Aarli JA. Striational antibodies in myasthenia gravis: reactivity and possible clinical significance. Arch Neurol 2005; 62(3): 442– 446.
26. Lindstrom J, Shelton D, Fujii Y. Myasthenia gravis. Adv Immunol 1988; 42: 233– 284.
27. Harcourt GC, Sommer N, Rothbard J, Willcox HN, Newsom‑ Davis J. A juxta‑ membrane epitope on the human acetylcholine receptor recognized by T cells in myasthenia gravis. J Clin Invest 1988; 82(4): 1295– 1300.
28. Melms A, Schalke BCG, Kirchner T, Müller‑ Hermelink HK, Albert E, Wekerle H. Thymus in myasthenia gravis: isolation of T‑lymphocyte lines specific for the nicotinic acetylcholine receptor from thymuses of myasthenic patients. J Clin Invest 1988; 81: 902– 908.
29. Ahlberg R, Yi Q, Pirskanen R, Matell G, Swe-rup C, Rieber EP et al. Treatment of myasthenia gravis with anti‑CD4 antibody: improvement correlates to decreased T cell autoreactivity. Neurology 1994; 44(9): 1732– 1737.
30. Wang ZY. Myasthenia in SCID mice grafted with myasthenic patient lymphocytes: role of CD4+ and CD8+ cells. Neurology 1999; 52(3): 484– 497.
31. Beissert S, Schwarz A, Schwarz T. Regulatory T cells. J Invest Dermatol 2006; 126(1): 15– 24.
32. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133(5): 775– 787. doi: 10.1016/ j.cell.2008.05.009.
33. Viglietta V, Baecher‑ Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004; 199(7): 971– 979.
34. Bystry RS, Aluvihare V, Welch KA, Kallikourdis M, Betz AG. B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2001; 2(12): 1126– 1132.
35. Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002; 2(6): 389– 400.
36. Aricha R, Feferman T, Fuchs S, Souroijon MC. Ex vivo regulatory T cells modelate experimental myasthenia gravis. J Immunol 2005; 175(12): 7898– 7904.
37. Gertel‑ Lapter S, Mizrachi K, Berrih‑ Aknin S, Fuchs S, Souroujon MC. Impairment of regulatory T cells in myasthenia gravis: studies in an experimental model. Autoimmun Rev 2013; 12(9): 894– 903. doi: 10.1016/ j.autrev.2013.03.009.
38. Balandina A, Lécart S, Dartevelle P, Saoudi A, Berrih‑ Aknin S. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 2005; 105(2): 735– 741.
39. Sun Y, Qiao J, Lu CZ, Zhao CB, Zhu XM, Xiao BG. Increase of circulating CD4+CD25+ T cells in myasthenia gravis patients with stability and thymectomy. Clin Immunol 2004; 112(3): 284– 289.
40. Zhang GX, Xiao BG, Bakhiet M, van der Meide P, Wigzell H, Link H et al. Both CD4+ and CD8+ T cells are essential to induce experimental autoimmune myasthenia gravis. J Exp Med 1996; 184(2): 349– 356.
41. Lisak RP, Laramore C, Zweiman B, Moskovitz A. In vitro synthesis of antibodies to acetylcholine receptor by peripheral blood mononuclear cells of patients with myasthenia gravis. Neurology 1983; 33(5): 604– 608.
42. Berrih‑ Aknin S, Ragheb S, Le Panse R, Lisak RP. Ectopic germinal centers, BAFf and anti‑B‑ cell therapy in myasthenia gravis. Autoimmun Rev 2013; 12(9): 885– 893. doi: 10.1016/ j.autrev.2013.03.011.
43. Wang ZY, Link H, Qiao J, Olsson T, Huang WX. Cell autoimmunity to acetylcholine receptor and its subunits in Lewis rats over the course of experimental autoimmune myasthenia gravis. J Neuroimmunol 1993; 45: 103– 112.
44. Vrolix K, Fraussen J, Losen M, Stevens J, Lazaridis K, Molenaar PC et al. Clonal heterogeneity of thymic B cells from early‑ onset myasthenia gravis patients with antibodies against the acetylcholine receptor. J Autoimmun 2014; 52: 101– 112. doi: 10.1016/ j.jaut.2013.12.008.
45. Kim JY, Yang Y, Moon JS, Lee EY, So SH, Lee HS et al. Serum BAFf expression in patients with myasthenia gravis. J Neuroimmunol 2008; 199(1– 2): 151– 154. doi: 10.1016/ j.jneuroim.2008.05.010.
46. Davidson A. Targeting BAFf in autoimmunity. Curr Opin Immunol 2010; 22(6): 732– 739. doi: 10.1016/ j.coi.2010.09.010.
47. Berrih‑ Aknin S, Ragheb S, Le Panse R, Lisak RP. Ectopic germinal centers, BAFf and anti‑B‑ cell therapy in myasthenia gravis. Autoimmun Rev 2013; 12: 885– 893. doi: 10.1016/ j.autrev.2013.03.011.
48. Mu L, Sun B, Kong Q, Wang J, Wang G, Zhang S et al. Disequilibrium of T helper type 1,2 and 17 cells and regulatory T cells during the development of experimental autoimmune myasthenia gravis. Immunology 2009; 128 (Suppl 1): 826– 836. doi: 10.1111/ j.1365‑ 2567.2009.03089.x.
49. Roche JC, Capablo JL, Larrad L, Gervas‑ Arruga J, Ara JR, Sanchez A et al. Increased serum interleukin‑17 levels in patients with myasthenia gravis. Muscle Nerve 2011; 44(2): 278– 280. doi: 10.1002/ mus.22070.
50. Wang Z, Wang W, Chen Y, Wei D. T helper type 17 cellsexpand in patients with myasthenia‑associated thymoma. Scand J Immunol 2012; 76: 54– 61. doi: 10.1111/ j.1365‑ 3083.2012.02703.x.
51. Cordiglieri C, Marolda R, Franzi S, Cappelletti C, Giardina C, Motta T et al. Innate immunity in myasthenia gravis thymus: pathogenic effects of Toll‑like receptor 4signaling on autoimmunity. J Autoimmun 2014; 52: 74– 89. doi: 10.1016/ j.jaut.2013.12.013.
52. Schaffert H, Pelz A, Saxena A, Losen M, Meisel A, Thiel A et al. IL‑17– producing CD4+ T cells contribute to the loss of B cell tolerance in experimental autoimmune myasthenia gravis. Eur J Immunol 2015; 45(5): 1339– 1347. doi: 10.1002/ eji.201445064.
53. Berrih‑ Aknin S, Le Panse R. Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun 2014; 52: 90– 100. doi: 10.1016/ j.jaut.2013.12.011.
54. Gradolatto A, Nazzal D, Truffault F, Bismuth J, Fa-del E, Foti M et al. Both Treg cells and Tconv cells aredefective in the myasthenia gravis thymus: roles of IL‑17 and TNF‑α. J Autoimmun 2014; 52: 53– 63. doi: 10.1016/ j.jaut.2013.12.015.
55. Valencia X, Stephens G, Goldbach‑ Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+CD25 T‑ regulatory cells. Blood 2006; 108(1): 253– 261.
56. Cohen‑ Kaminski S, Delattre RM, Devergne O, Klingel‑ Schmitt I, Emilie D, Galanaud P et al. High IL‑6 gene expression and production by cultured human thymic epithelial cells from patients with myasthenia gravis. Ann N Y Acad Sci 1993; 681: 97– 99.
57. Endo S, Hasegawa T, Sato Y. Inhibition of IL‑6 overproduction by steroid treatment before transsternal thymectomy for myasthenia gravis: does it help stabilize perioperative condition? Eur J Neurol 2005; 12(10): 768– 773.
58. Takatsu K. Cytokines involved in B cell differentiation and their sites of action. Proc Soc Exp Biol Med 1997; 215(2): 121– 133.
59. Aricha R, Mizrachi K, Fuchs S, Souroujon MC. Blocking of IL‑6 suppresses experimental autoimmune myasthenia gravis. J Autoimmun 2011; 36(2): 135– 141. doi: 10.1016/ j.jaut.2010.12.001.
60. Deng C, Goluczko E, Tuzun E, Yang H, Christa-doss P. Resistance to experimental autoimmune myasthenia gravis in IL‑6- deficient mice is associated with reduced germinal center formation and reduced C3 production. J Immunol 2002; 169(2): 1077– 1083.
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