Advertisement

Thymoma-Associated Myasthenia Gravis

  • Alexander Marx
  • Philipp Ströbel
  • Cleo-Aron Weis
Chapter
Part of the Current Clinical Neurology book series (CCNEU)

Abstract

Thymoma-associated MG (TAMG) is almost always due to autoantibodies that recognize soluble nicotinic acetylcholine receptors (AChR). Alongside early-onset MG (EOMG) and late-onset MG (LOMG), TAMG represents the smallest subset (10–15%) among the anti-AChR MG subtypes. TAMG-associated thymomas are unique among cancers because almost all maintain thymus-like features, including intratumorous thymopoiesis. Therefore, it is thought that key immune tolerance-inducing mechanisms of the normal thymus go awry in thymomas. We describe the widely accepted three-step pathogenetic model of TAMG that comprises (1) intratumorous biased positive selection of T cells that preferentially recognizes skeletal muscle autoantigens, (2) intratumorous defective negative selection of potentially autoreactive effector T cells and deficient generation of regulatory T cells, and (3) the extra-tumorous, self-perpetuating activation of T and B cells and autoantibody-producing cells following enigmatic triggers. Molecular features underlying the three-step autoimmunization are also addressed. Current pathogenetic models of EOMG and LOMG are described for comparison.

Keywords

Myasthenia gravis Thymoma Thymus Thymic follicular hyperplasia Autoimmune regulator AIRE CTLA4 Myoid cell 

References

  1. 1.
    Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14(10):1023–36.PubMedCrossRefGoogle Scholar
  3. 3.
    Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain. 2008;131(Pt 7):1940–52.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kaminski HJ. Seronegative myasthenia gravis-a vanishing disorder? JAMA Neurol. 2016;73(9):1055–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Leite MI, Strobel P, Jones M, Micklem K, Moritz R, Gold R, et al. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol. 2005;57(3):444–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classifications—authors’ reply. Lancet Neurol. 2016;15(4):357–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Hu B, Simon-Keller K, Kuffer S, Strobel P, Braun T, Marx A, et al. Myf5 and myogenin in the development of thymic myoid cells—implications for a murine in vivo model of myasthenia gravis. Exp Neurol. 2016;277:76–85.PubMedCrossRefGoogle Scholar
  8. 8.
    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;52:139–45.PubMedCrossRefGoogle Scholar
  9. 9.
    Strobel P, Moritz R, Leite MI, Willcox N, Chuang WY, Gold R, et al. The ageing and myasthenic thymus: a morphometric study validating a standard procedure in the histological workup of thymic specimens. J Neuroimmunol. 2008;201–202:64–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Chuang WY, Strobel P, Bohlender-Willke AL, Rieckmann P, Nix W, Schalke B, et al. Late-onset myasthenia gravis—CTLA4(low) genotype association and low-for-age thymic output of naive T cells. J Autoimmun. 2014;52:122–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Skeie GO, Romi F. Paraneoplastic myasthenia gravis: immunological and clinical aspects. Eur J Neurol. 2008;15(10):1029–33.PubMedCrossRefGoogle Scholar
  12. 12.
    Dalla Costa M, Mangano FA, Betterle C. Thymic hyperplasia in patients with Graves’ disease. J Endocrinol Investig. 2014;37(12):1175–9.CrossRefGoogle Scholar
  13. 13.
    Middleton G, Schoch EM. The prevalence of human thymic lymphoid follicles is lower in suicides. Virchows Arch. 2000;436(2):127–30.PubMedCrossRefGoogle Scholar
  14. 14.
    Leite MI, Jones M, Strobel P, Marx A, Gold R, Niks E, et al. Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Am J Pathol. 2007;171(3):893–905.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kirchner T, Schalke B, Melms A, von Kugelgen T, Muller-Hermelink HK. Immunohistological patterns of non-neoplastic changes in the thymus in myasthenia gravis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1986;52(3):237–57.PubMedCrossRefGoogle Scholar
  16. 16.
    Curnow J, Corlett L, Willcox N, Vincent A. Presentation by myoblasts of an epitope from endogenous acetylcholine receptor indicates a potential role in the spreading of the immune response. J Neuroimmunol. 2001;115(1–2):127–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Geuder KI, Marx A, Witzemann V, Schalke B, Toyka K, Kirchner T, et al. Pathogenetic significance of fetal-type acetylcholine receptors on thymic myoid cells in myasthenia gravis. Dev Immunol. 1992;2(2):69–75.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Schluep M, Willcox N, Vincent A, Dhoot GK, Newsom-Davis J. Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study. Ann Neurol. 1987;22(2):212–22.PubMedCrossRefGoogle Scholar
  19. 19.
    Marx A, Osborn M, Tzartos S, Geuder KI, Schalke B, Nix W, et al. A striational muscle antigen and myasthenia gravis-associated thymomas share an acetylcholine-receptor epitope. Dev Immunol. 1992;2(2):77–84.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Schalke BC, Mertens HG, Kirchner T, Wegener S, Muller-Hermelink HK. Long-term treatment with azathioprine abolishes thymic lymphoid follicular hyperplasia in myasthenia gravis. Lancet. 1987;2(8560):682.PubMedCrossRefGoogle Scholar
  21. 21.
    Marx A, Pfister F, Schalke B, Nix W, Strobel P. Thymus pathology observed in the MGTX trial. Ann N Y Acad Sci. 2012;1275:92–100.PubMedCrossRefGoogle Scholar
  22. 22.
    Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, et al. Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. Ann Neurol. 2012;72(6):927–35.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Renton AE, Pliner HA, Provenzano C, Evoli A, Ricciardi R, Nalls MA, et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 2015;72(4):396–404.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Vincent A, Scadding GK, Thomas HC, Newsom-Davis J. In-vitro synthesis of anti-acetylcholine-receptor antibody by thymic lymphocytes in myasthenia gravis. Lancet. 1978;1(8059):305–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Berrih-Aknin S. Myasthenia gravis: paradox versus paradigm in autoimmunity. J Autoimmun. 2014;52:1–28.PubMedCrossRefGoogle Scholar
  26. 26.
    Gradolatto A, Nazzal D, Truffault F, Bismuth J, Fadel E, Foti M, et al. Both Treg cells and Tconv cells are defective in the myasthenia gravis thymus: roles of IL-17 and TNF-alpha. J Autoimmun. 2014;52:53–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Hohlfeld R, Wekerle H. Reflections on the “intrathymic pathogenesis” of myasthenia gravis. J Neuroimmunol. 2008;201–202:21–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511–22.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Marx A, Chan JK, Coindre JM, Detterbeck F, Girard N, Harris NL, et al. The 2015 World Health Organization classification of tumors of the thymus: continuity and changes. J Thorac Oncol. 2015;10(10):1383–95.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    IARC, editor. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. Geneva: WHO; 2015.Google Scholar
  31. 31.
    Strobel P, Murumagi A, Klein R, Luster M, Lahti M, Krohn K, et al. Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J Pathol. 2007;211(5):563–71.PubMedCrossRefGoogle Scholar
  32. 32.
    Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms. J Thorac Oncol. 2011;6(7 Suppl 3):S1710–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Weis CA, Yao X, Deng Y, Detterbeck FC, Marino M, Nicholson AG, et al. The impact of thymoma histotype on prognosis in a worldwide database. J Thorac Oncol. 2015;10(2):367–72.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kondo K. The International Association for the Study of Lung Cancer/the International Thymic Malignancies Interest Group proposal for the TNM staging systems for thymic epithelial tumors and large-scale retrospective data. J Thorac Dis. 2016;8(8):1856–8.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Meager A, Wadhwa M, Dilger P, Bird C, Thorpe R, Newsom-Davis J, et al. 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. 2003;132(1):128–36.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Smith SM, Ossa-Gomez LJ. A quantitative histologic comparison of the thymus in 100 healthy and diseased adults. Am J Clin Pathol. 1981;76(5):657–65.PubMedCrossRefGoogle Scholar
  37. 37.
    Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, et al. Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature. 2005;436(7054):1181–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Roxanis I, Micklem K, McConville J, Newsom-Davis J, Willcox N. Thymic myoid cells and germinal center formation in myasthenia gravis; possible roles in pathogenesis. J Neuroimmunol. 2002;125(1–2):185–97.PubMedCrossRefGoogle Scholar
  39. 39.
    Romi F, Skeie GO, Aarli JA, Gilhus NE. Muscle autoantibodies in subgroups of myasthenia gravis patients. J Neurol. 2000;247(5):369–75.PubMedCrossRefGoogle Scholar
  40. 40.
    Klein R, Marx A, Strobel P, Schalke B, Nix W, Willcox N. Autoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. Hum Immunol. 2013;74(9):1184–93.PubMedCrossRefGoogle Scholar
  41. 41.
    Zouridakis M, Zisimopoulou P, Poulas K, Tzartos SJ. Recent advances in understanding the structure of nicotinic acetylcholine receptors. IUBMB Life. 2009;61(4):407–23.PubMedCrossRefGoogle Scholar
  42. 42.
    Wakkach A, Poea S, Chastre E, Gespach C, Lecerf F, De La Porte S, et al. Establishment of a human thymic myoid cell line. Phenotypic and functional characteristics. Am J Pathol. 1999;155(4):1229–40.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Fraterman S, Khurana TS, Rubinstein NA. Identification of acetylcholine receptor subunits differentially expressed in singly and multiply innervated fibers of extraocular muscles. Invest Ophthalmol Vis Sci. 2006;47(9):3828–34.PubMedCrossRefGoogle Scholar
  44. 44.
    Tzartos SJ, Lindstrom JM. Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits. Proc Natl Acad Sci U S A. 1980;77(2):755–9.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Siara J, Rudel R, Marx A. Absence of acetylcholine-induced current in epithelial cells from thymus glands and thymomas of myasthenia gravis patients. Neurology. 1991;41(1):128–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Giraud M, Taubert R, Vandiedonck C, Ke X, Levi-Strauss M, Pagani F, et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature. 2007;448(7156):934–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Rodriguez Cruz PM, Al-Hajjar M, Huda S, Jacobson L, Woodhall M, Jayawant S, et al. Clinical features and diagnostic usefulness of antibodies to clustered acetylcholine receptors in the diagnosis of seronegative myasthenia gravis. JAMA Neurol. 2015;72(6):642–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Mygland A, Aarli JA, Matre R, Gilhus NE. Ryanodine receptor antibodies related to severity of thymoma associated myasthenia gravis. J Neurol Neurosurg Psychiatry. 1994;57(7):843–6.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Skeie GO, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol Scand Suppl. 2006;183:19–23.PubMedCrossRefGoogle Scholar
  50. 50.
    Suzuki S, Utsugisawa K, Nagane Y, Suzuki N. Three types of striational antibodies in myasthenia gravis. Autoimmun Dis. 2011;2011:740583.Google Scholar
  51. 51.
    Imai T, Tsuda E, Toyoshima T, Yoshikawa H, Motomura M, Shimohama S. Anti-ryanodine receptor-positive acetylcholine receptor-negative myasthenia gravis: evidence of impaired excitation-contraction coupling. Muscle Nerve. 2011;43(2):294–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Aarli JA. Myasthenia gravis in the elderly: is it different? Ann N Y Acad Sci. 2008;1132:238–43.PubMedCrossRefGoogle Scholar
  53. 53.
    Romi F, Skeie GO, Vedeler C, Aarli JA, Zorzato F, Gilhus NE. Complement activation by titin and ryanodine receptor autoantibodies in myasthenia gravis. A study of IgG subclasses and clinical correlations. J Neuroimmunol. 2000;111(1–2):169–76.PubMedCrossRefGoogle Scholar
  54. 54.
    Wolff AS, Karner J, Owe JF, Oftedal BE, Gilhus NE, Erichsen MM, et al. Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors. J Immunol. 2014;193(8):3880–90.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010;207(2):299–308.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Meyer S, Woodward M, Hertel C, Vlaicu P, Haque Y, Karner J, et al. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell. 2016;166(3):582–95.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology. 1976;26(11):1054–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Aarli JA, Stefansson K, Marton LS, Wollmann RL. Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin. Clin Exp Immunol. 1990;82(2):284–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Mygland A, Tysnes OB, Matre R, Volpe P, Aarli JA, Gilhus NE. Ryanodine receptor autoantibodies in myasthenia gravis patients with a thymoma. Ann Neurol. 1992;32(4):589–91.PubMedCrossRefGoogle Scholar
  60. 60.
    Marx A, O’Connor R, Tzartos S, Kalies I, Kirchner T, Muller-Hermelink HK. Acetylcholine receptor epitope in proteins of myasthenia gravis-associated thymomas and non-thymic tissues. Thymus. 1989;14(1–3):171–8.PubMedGoogle Scholar
  61. 61.
    Romi F, Bo L, Skeie GO, Myking A, Aarli JA, Gilhus NE. Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules. J Neuroimmunol. 2002;128(1–2):82–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Mygland A, Kuwajima G, Mikoshiba K, Tysnes OB, Aarli JA, Gilhus NE. Thymomas express epitopes shared by the ryanodine receptor. J Neuroimmunol. 1995;62(1):79–83.PubMedCrossRefGoogle Scholar
  63. 63.
    Kusner LL, Mygland A, Kaminski HJ. Ryanodine receptor gene expression thymomas. Muscle Nerve. 1998;21(10):1299–303.PubMedCrossRefGoogle Scholar
  64. 64.
    Kirchner T, Hoppe F, Muller-Hermelink HK, Schalke B, Tzartos S. Acetylcholine receptor epitopes on epithelial cells of thymoma in myasthenia gravis. Lancet (London, England). 1987;1(8526):218.CrossRefGoogle Scholar
  65. 65.
    Marx A, Wilisch A, Schultz A, Greiner A, Magi B, Pallini V, et al. Expression of neurofilaments and of a titin epitope in thymic epithelial tumors. Implications for the pathogenesis of myasthenia gravis. Am J Pathol. 1996;148(6):1839–50.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Schultz A, Hoffacker V, Wilisch A, Nix W, Gold R, Schalke B, et al. Neurofilament is an autoantigenic determinant in myasthenia gravis. Ann Neurol. 1999;46(2):167–75.PubMedCrossRefGoogle Scholar
  67. 67.
    Hohlfeld R, Toyka KV, Heininger K, Grosse-Wilde H, Kalies I. Autoimmune human T lymphocytes specific for acetylcholine receptor. Nature. 1984;310(5974):244–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Nagvekar N, Moody AM, Moss P, Roxanis I, Curnow J, Beeson D, et al. A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes. J Clin Invest. 1998;101(10):2268–77.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Marx A, Willcox N, Leite MI, Chuang WY, Schalke B, Nix W, et al. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity. 2010;43(5–6):413–27.PubMedCrossRefGoogle Scholar
  70. 70.
    Sommer N, Harcourt GC, Willcox N, Beeson D, Newsom-Davis J. Acetylcholine receptor-reactive T lymphocytes from healthy subjects and myasthenia gravis patients. Neurology. 1991;41(8):1270–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Melms A, Malcherek G, Gern U, Wietholter H, Muller CA, Schoepfer R, et al. T cells from normal and myasthenic individuals recognize the human acetylcholine receptor: heterogeneity of antigenic sites on the alpha-subunit. Ann Neurol. 1992;31(3):311–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Balandina A, Lecart 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):735–41.PubMedCrossRefGoogle Scholar
  73. 73.
    Alahgholi-Hajibehzad M, Oflazer P, Aysal F, Durmus H, Gulsen-Parman Y, Marx A, et al. Regulatory function of CD4+CD25++ T cells in patients with myasthenia gravis is associated with phenotypic changes and STAT5 signaling: 1,25-dihydroxyvitamin D3 modulates the suppressor activity. J Neuroimmunol. 2015;281:51–60.PubMedCrossRefGoogle Scholar
  74. 74.
    Buckley C, Oger J, Clover L, Tuzun E, Carpenter K, Jackson M, et al. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol. 2001;50(1):73–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Strobel P, Helmreich M, Menioudakis G, Lewin SR, Rudiger T, Bauer A, et al. Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood. 2002;100(1):159–66.PubMedCrossRefGoogle Scholar
  76. 76.
    Strobel P, Rosenwald A, Beyersdorf N, Kerkau T, Elert O, Murumagi A, et al. Selective loss of regulatory T cells in thymomas. Ann Neurol. 2004;56(6):901–4.PubMedCrossRefGoogle Scholar
  77. 77.
    Maniaol AH, Elsais A, Lorentzen AR, Owe JF, Viken MK, Saether H, et al. Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population. PLoS One. 2012;7(5):e36603.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Seldin MF, Alkhairy OK, Lee AT, Lamb JA, Sussman J, Pirskanen-Matell R, et al. Genome-wide Association Study of late-onset myasthenia gravis: confirmation of TNFRSF11A, and identification of ZBTB10 and three distinct HLA associations. Mol Med. 2015;21(1):769–81.PubMedCentralCrossRefGoogle Scholar
  79. 79.
    Hoffacker V, Schultz A, Tiesinga JJ, Gold R, Schalke B, Nix W, et al. Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood. 2000;96(12):3872–9.PubMedGoogle Scholar
  80. 80.
    Tackenberg B, Schlegel K, Happel M, Eienbroker C, Gellert K, Oertel WH, et al. Expanded TCR Vbeta subsets of CD8(+) T-cells in late-onset myasthenia gravis: novel parallels with thymoma patients. J Neuroimmunol. 2009;216(1–2):85–91.PubMedCrossRefGoogle Scholar
  81. 81.
    Cavalcante P, Cufi P, Mantegazza R, Berrih-Aknin S, Bernasconi P, Le Panse R. Etiology of myasthenia gravis: innate immunity signature in pathological thymus. Autoimmun Rev. 2013;12(9):863–74.PubMedCrossRefGoogle Scholar
  82. 82.
    Cavalcante P, Serafini B, Rosicarelli B, Maggi L, Barberis M, Antozzi C, et al. Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol. 2010;67(6):726–38.PubMedGoogle Scholar
  83. 83.
    Meyer M, Hols AK, Liersch B, Leistner R, Gellert K, Schalke B, et al. Lack of evidence for Epstein-Barr virus infection in myasthenia gravis thymus. Ann Neurol. 2011;70(3):515–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Kakalacheva K, Maurer MA, Tackenberg B, Munz C, Willcox N, Lunemann JD. Intrathymic Epstein-Barr virus infection is not a prominent feature of myasthenia gravis. Ann Neurol. 2011;70(3):508–14.PubMedCrossRefGoogle Scholar
  85. 85.
    Alkhawajah NM, Oger J. Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing. Muscle Nerve. 2013;48(5):705–10.PubMedCrossRefGoogle Scholar
  86. 86.
    Nacu A, Andersen JB, Lisnic V, Owe JF, Gilhus NE. Complicating autoimmune diseases in myasthenia gravis: a review. Autoimmunity. 2015;48(6):362–8.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Bucknall RC, Dixon ASJ, Glick EN, Woodland J, Zutshi DW. Myasthenia gravis associated with penicillamine treatment for rheumatoid arthritis. Br Med J. 1975;1(5958):600–2.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Poulas K, Koutsouraki E, Kordas G, Kokla A, Tzartos SJ. Anti-MuSK- and anti-AChR-positive myasthenia gravis induced by d-penicillamine. J Neuroimmunol. 2012;250(1–2):94–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis—autoantibody characteristics and their implications for therapy. Nat Rev Neurol. 2016;12(5):259–68.PubMedCrossRefGoogle Scholar
  90. 90.
    Sims GP, Shiono H, Willcox N, Stott DI. Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis. J Immunol. 2001;167(4):1935–44.PubMedCrossRefGoogle Scholar
  91. 91.
    Meinl E, Klinkert WE, Wekerle H. 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. 1991;139(5):995–1008.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Robinet M, Maillard S, Cron MA, Berrih-Aknin S, Le Panse R. Review on toll-like receptor activation in myasthenia gravis: application to the development of new experimental models. Clin Rev Allergy Immunol. 2017;52(1):133–47.PubMedCrossRefGoogle Scholar
  93. 93.
    Weiss JM, Robinet M, Aricha R, Cufi P, Villeret B, Lantner F, et al. Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis. Oncotarget. 2016;7(7):7550–62.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Wekerle H, Ketelsen UP. Intrathymic pathogenesis and dual genetic control of myasthenia gravis. Lancet. 1977;1(8013):678–80.PubMedCrossRefGoogle Scholar
  95. 95.
    Weinberg CB, Hall ZW. Antibodies from patients with myasthenia gravis recognize determinants unique to extrajunctional acetylcholine receptors. Proc Natl Acad Sci U S A. 1979;76(1):504–8.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Kirchner T, Hoppe F, Schalke B, Muller-Hermelink HK. Microenvironment of thymic myoid cells in myasthenia gravis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1988;54(5):295–302.PubMedGoogle Scholar
  97. 97.
    Abdou NI, Lisak RP, Zweiman B, Abrahamsohn I, Penn AS. The thymus in myasthenia gravis. Evidence for altered cell populations. N Engl J Med. 1974;291(24):1271–5.PubMedCrossRefGoogle Scholar
  98. 98.
    Gomez AM, Vrolix K, Martinez-Martinez P, Molenaar PC, Phernambucq M, van der Esch E, et al. Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. J Immunol. 2011;186(4):2503–13.PubMedCrossRefGoogle Scholar
  99. 99.
    Willcox HN, Newsom-Davis J, Calder LR. Cell types required for anti-acetylcholine receptor antibody synthesis by cultured thymocytes and blood lymphocytes in myasthenia gravis. Clin Exp Immunol. 1984;58(1):97–106.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Eimoto T, Kusano T, Ando K, Kikuchi M, Shirakusa T, Kawanami S. Nonneoplastic and nonhyperplastic thymus in myasthenia gravis. An immunohistochemical study with double immunoenzyme labeling of basement membrane and cellular components. Am J Clin Pathol. 1990;94(1):36–43.Google Scholar
  101. 101.
    Roxanis I, Micklem K, Willcox N. True epithelial hyperplasia in the thymus of early-onset myasthenia gravis patients: implications for immunopathogenesis. J Neuroimmunol. 2001;112(1–2):163–73.PubMedCrossRefGoogle Scholar
  102. 102.
    Wakkach A, Guyon T, Bruand C, Tzartos S, Cohen-Kaminsky S, Berrih-Aknin S. Expression of acetylcholine receptor genes in human thymic epithelial cells: implications for myasthenia gravis. J Immunol. 1996;157(8):3752–60.PubMedGoogle Scholar
  103. 103.
    Poea-Guyon S, Christadoss P, Le Panse R, Guyon T, De Baets M, Wakkach A, et al. Effects of cytokines on acetylcholine receptor expression: implications for myasthenia gravis. J Immunol. 2005;174(10):5941–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Gilhus NE, Matre R. Fc gamma receptors and HLA-DR antigens on thymus cells in myasthenia gravis. J Neuroimmunol. 1986;10(3):271–8.PubMedCrossRefGoogle Scholar
  105. 105.
    Chilosi M, Iannucci A, Fiore-Donati L, Tridente G, Pampanin M, Pizzolo G, et al. Myasthenia gravis: immunohistological heterogeneity in microenvironmental organization of hyperplastic and neoplastic thymuses suggesting different mechanisms of tolerance breakdown. J Neuroimmunol. 1986;11(3):191–204.PubMedCrossRefGoogle Scholar
  106. 106.
    Cufi P, Dragin N, Ruhlmann N, Weiss JM, Fadel E, Serraf A, et al. Central role of interferon-beta in thymic events leading to myasthenia gravis. J Autoimmun. 2014;52:44–52.PubMedCrossRefGoogle Scholar
  107. 107.
    Berrih-Aknin S, Ruhlmann N, Bismuth J, Cizeron-Clairac G, Zelman E, Shachar I, et al. CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia. Ann Neurol. 2009;66(4):521–31.PubMedCrossRefGoogle Scholar
  108. 108.
    Weiss JM, Cufi P, Bismuth J, Eymard B, Fadel E, Berrih-Aknin S, et al. SDF-1/CXCL12 recruits B cells and antigen-presenting cells to the thymus of autoimmune myasthenia gravis patients. Immunobiology. 2013;218(3):373–81.PubMedCrossRefGoogle Scholar
  109. 109.
    Bernasconi P, Barberis M, Baggi F, Passerini L, Cannone M, Arnoldi E, et al. Increased toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution. Am J Pathol. 2005;167(1):129–39.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Meraouna A, Cizeron-Clairac G, Panse RL, Bismuth J, Truffault F, Tallaksen C, et al. The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. Blood. 2006;108(2):432–40.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Thangarajh M, Masterman T, Helgeland L, Rot U, Jonsson MV, Eide GE, et al. The thymus is a source of B-cell-survival factors-APRIL and BAFF-in myasthenia gravis. J Neuroimmunol. 2006;178(1–2):161–6.PubMedCrossRefGoogle Scholar
  112. 112.
    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):885–93.PubMedCrossRefGoogle Scholar
  113. 113.
    Safar D, Aime C, Cohen-Kaminsky S, Berrih-Aknin S. Antibodies to thymic epithelial cells in myasthenia gravis. J Neuroimmunol. 1991;35(1–3):101–10.PubMedCrossRefGoogle Scholar
  114. 114.
    Willcox N, Leite MI, Kadota Y, Jones M, Meager A, Subrahmanyam P, et al. Autoimmunizing mechanisms in thymoma and thymus. Ann N Y Acad Sci. 2008;1132:163–73.PubMedCrossRefGoogle Scholar
  115. 115.
    Vincent A, Willcox N. The role of T-cells in the initiation of autoantibody responses in thymoma patients. Pathol Res Pract. 1999;195(8):535–40.PubMedCrossRefGoogle Scholar
  116. 116.
    Marx A, Porubsky S, Belharazem D, Saruhan-Direskeneli G, Schalke B, Strobel P, et al. Thymoma related myasthenia gravis in humans and potential animal models. Exp Neurol. 2015;270:55–65.PubMedCrossRefGoogle Scholar
  117. 117.
    Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Strobel P. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev. 2013;12(9):875–84.PubMedCrossRefGoogle Scholar
  118. 118.
    Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol. 2011;41(6):1517–27.PubMedCrossRefGoogle Scholar
  119. 119.
    Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007;8(4):351–8.PubMedCrossRefGoogle Scholar
  120. 120.
    Buckley C, Douek D, Newsom-Davis J, Vincent A, Willcox N. Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol. 2001;50(1):64–72.PubMedCrossRefGoogle Scholar
  121. 121.
    Strobel P, Chuang WY, Chuvpilo S, Zettl A, Katzenberger T, Kalbacher H, et al. Common cellular and diverse genetic basis of thymoma-associated myasthenia gravis: role of MHC class II and AIRE genes and genetic polymorphisms. Ann N Y Acad Sci. 2008;1132:143–56.PubMedCrossRefGoogle Scholar
  122. 122.
    Berezovsky IN, Esipova NG, Tumanyan VG. Hierarchy of regions of amino acid sequence with respect to their role in the protein spatial structure. J Comput Biol. 2000;7(1–2):183–92.PubMedCrossRefGoogle Scholar
  123. 123.
    Willcox N, Schluep M, Ritter MA, Schuurman HJ, Newsom-Davis J, Christensson B. Myasthenic and nonmyasthenic thymoma. An expansion of a minor cortical epithelial cell subset? Am J Pathol. 1987;127(3):447–60.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Chuang WY, Strobel P, Belharazem D, Rieckmann P, Toyka KV, Nix W, et al. The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis. Genes Immun. 2009;10(8):667–72.PubMedCrossRefGoogle Scholar
  125. 125.
    Chuang WY, Strobel P, Gold R, Nix W, Schalke B, Kiefer R, et al. A CTLA4 high genotype is associated with myasthenia gravis in thymoma patients. Ann Neurol. 2005;58(4):644–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Zettl A, Strobel P, Wagner K, Katzenberger T, Ott G, Rosenwald A, et al. Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol. 2000;157(1):257–66.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010;10:46.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Casetta I, Groppo E, De Gennaro R, Cesnik E,Piccolo L, Volpato S, et al. Myasthenia gravis: a changing pattern of incidence. J Neurol. 2010;257(12):2015–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Pedersen EG, Hallas J, Hansen K, Jensen PE, Gaist D. Late-onset myasthenia not on the increase: a nationwide register study in Denmark, 1996–2009. Eur J Neurol. 2013;20(2):309–14.PubMedCrossRefGoogle Scholar
  130. 130.
    Somnier FE. Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis. Neurology. 2005;65(6):928–30.PubMedCrossRefGoogle Scholar
  131. 131.
    Tackenberg B, Nitschke M, Willcox N, Ziegler A, Nessler S, Schumm F, et al. CD45 isoform expression in autoimmune myasthenia gravis. Autoimmunity. 2003;36(2):117–21.PubMedCrossRefGoogle Scholar
  132. 132.
    Romi F, Gilhus NE, Varhaug JE, Myking A, Skeie GO, Aarli JA. Thymectomy and anti-muscle autoantibodies in late-onset myasthenia gravis. Eur J Neurol. 2002;9(1):55–61.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Alexander Marx
    • 1
  • Philipp Ströbel
    • 2
  • Cleo-Aron Weis
    • 1
  1. 1.Department of PathologyUniversity Medical Centre Mannheim, University of HeidelbergMannheimGermany
  2. 2.Department of PathologyUniversity Medical Center Göttingen, University of GöttingenGöttingenGermany

Personalised recommendations