Invited Review
The thymus in myasthenia gravis: Site of “innate autoimmunity”?
Paola Cavalcante PhD,
Rozen Le Panse PhD,
Sonia Berrih-aknin PhD,
Lorenzo Maggi MD,
Carlo Antozzi MD,
Fulvio Baggi PhD,
Pia Bernasconi PhD,
Renato Mantegazza MD,
Paola Cavalcante PhD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorRozen Le Panse PhD
Unité mixte de recherche, CNRS UMR7215/INSERM U974/UPMC/AIM, Thérapie des maladies du muscle strié, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
Search for more papers by this authorSonia Berrih-aknin PhD
Unité mixte de recherche, CNRS UMR7215/INSERM U974/UPMC/AIM, Thérapie des maladies du muscle strié, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
Search for more papers by this authorLorenzo Maggi MD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorCarlo Antozzi MD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorFulvio Baggi PhD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorPia Bernasconi PhD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorCorresponding Author
Renato Mantegazza MD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, ItalySearch for more papers by this authorPaola Cavalcante PhD,
Rozen Le Panse PhD,
Sonia Berrih-aknin PhD,
Lorenzo Maggi MD,
Carlo Antozzi MD,
Fulvio Baggi PhD,
Pia Bernasconi PhD,
Renato Mantegazza MD,
Paola Cavalcante PhD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorRozen Le Panse PhD
Unité mixte de recherche, CNRS UMR7215/INSERM U974/UPMC/AIM, Thérapie des maladies du muscle strié, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
Search for more papers by this authorSonia Berrih-aknin PhD
Unité mixte de recherche, CNRS UMR7215/INSERM U974/UPMC/AIM, Thérapie des maladies du muscle strié, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
Search for more papers by this authorLorenzo Maggi MD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorCarlo Antozzi MD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorFulvio Baggi PhD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorPia Bernasconi PhD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Search for more papers by this authorCorresponding Author
Renato Mantegazza MD
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, Italy
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico “Carlo Besta,” Via Celoria 11, 20133 Milan, ItalySearch for more papers by this authorAbstract
Myasthenia gravis (MG) is an autoimmune disorder caused, in most cases, by autoantibodies against components of the neuromuscular junction, frequently the acetylcholine receptor (AChR), and less often the muscle-specific kinase receptor. The thymus plays a major role in the pathogenesis of MG with anti-AChR antibodies: it shows marked pathologic alterations (hyperplastic or tumoral) in most AChR-positive patients and contains the elements required to initiate and sustain an autoimmune reaction (AChR autoantigen, AChR-specific T cells, and autoantibody-secreting plasma cells). In this study we review early and more recent findings implicating the thymus as site of AChR autosensitization in MG and briefly discuss the therapeutic role of thymectomy. We also summarize data showing that the MG thymus is in a state of chronic inflammation, and we review emerging evidence of a viral contribution to the onset and maintenance of the thymic autoimmune response. Muscle Nerve, 2011
REFERENCES
- 1 Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol 2010; 10: 46.
- 2 Mantegazza R, Baggi F, Antozzi C, Confalonieri P, Morandi L, Bernasconi P, et al. Myasthenia gravis (MG): epidemiological data and prognostic factors. Ann NY Acad Sci 2003; 998: 413–423.
- 3 Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2002; 2: 797–804.
- 4 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: 1054–1059.
- 5 Sahashi K, Engel AG, Lambert EH, Howard FM Jr. Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis. J Neuropathol Exp Neurol 1980; 39: 160–172.
- 6 Piddlesden SJ, Jiang S, Levin JL, Vincent A, Morgan BP. Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis. J Neuroimmunol 1996; 71: 173–177.
- 7 Drachman DB, Angus CW, Adams RN, Michelson JD, Hoffman GJ. Myasthenia antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med 1978; 298: 1116–1122.
- 8 Gomez CM, Richman DP. Anti-acetylcholine receptor antibodies directed against the alpha-bungarotoxin binding site induce a unique form of experimental myasthenia. Proc Natl Acad Sci USA 1983; 80: 4089–4093.
- 9 Lennon VA, Seybold ME, Lindstrom JM, Cochrane C, Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med 1978; 147: 973–983.
- 10 Biesecker G, Gomez CM. Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6. J Immunol 1989; 142: 2654–2659.
- 11 Christadoss P. C5 gene influences the development of murine myasthenia gravis. J Immunol 1988; 140: 2589–2592.
- 12 Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001; 7: 365–368.
- 13 Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003; 126: 2304–2311.
- 14 Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003; 60: 1978–1980.
- 15 McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004; 55: 580–584.
- 16 Vincent A, McConville J, Farrugia ME, Newsom-Dawis J. Seronegative myasthenia gravis. Semin Neurol 2004; 24: 125–133.
- 17 Farrugia ME, Bonifati DM, Clover L, Cossins J, Beeson D, Vincent A. Effect of sera from AChR-antibody negative myasthenia gravis patients on AChR and MuSK in cell cultures. J Neuroimmunol 2007; 185: 136–144.
- 18 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: 1940–1952.
- 19 Gautel M, Lakey A, Barlow DP, Holmes Z, Scales S, Leonard K, et al. Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin. Neurology 1993; 43: 1581–1585.
- 20 Baggi F, Andreetta F, Antozzi C, Simoncini O, Confalonieri P, Labeit S, et al. Anti-titin and antiryanodine receptor antibodies in myasthenia gravis patients with thymoma. Ann NY Acad Sci 1998; 841: 538–541.
- 21 Maggi L, Andreetta F, Antozzi C, Baggi F, Bernasconi P, Cavalcante P, et al. Thymoma-associated myasthenia gravis: outcome, clinical and pathological correlations in 197 on a 20-year experience. J Neuroimmunol 2008; 15: 202: 237–244.
- 22 Murphy J, Murphy SF. Myasthenia gravis in identical twins. Neurology 1986; 36: 78–80.
- 23 Machens A, Loliger C, Pichlmeier U, Emskotter T, Busch C, Izbicki JR. Correlation of thymic pathology with HLA in myasthenia gravis. Clin Immunol 1999; 91: 296–301.
- 24 Vandiedonck C, Giraud M, Garchon HJ. Genetics of autoimmune myasthenia gravis: the multifaceted contribution of the HLA complex. J Autoimmun 2005; 25: 6–11.
- 25 Vandiedonck C, Beaurain G, Giraud M, Hue-Beauvais C, Eymard B, Tranchant C, et al. Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia. Proc Natl Acad Sci USA 2004; 101: 1564–1569.
- 26 Vieira ML, Caillat-Zucman S, Gajdos P, Cohen-Kaminsky S, Casteur A, Bach JF. Identification of genomic typing non-DR3 HLA class II genes associated myasthenia gravis. J Neuroimmunol 1993; 47: 115–122.
- 27 Vandiedonck C, Raffoux C, Eymard B, Krumeich CS, Gajdos P, Garchon HJ. Association of HLA-A in autoimmune myasthenia gravis with thymoma. J Neuroimmunol 2009; 210: 120–123.
- 28 Giraud M, Vandiedonck C, Garchon HJ. Genetic factors in autoimmune myasthenia gravis. Ann NY Acad Sci 2008; 1132: 180–192.
- 29 Garchon HJ, Djabiri F, Viard JP, Gajdos P, Bach JF. Involvement of human muscle acetylcholine receptor alpha-subunit gene (CHRNA) in susceptibility to myasthenia gravis. Proc Natl Acad Sci USA 1994; 91: 4668–4672.
- 30 Giraud M, Taubert R, Vandiedonck C, Ke X, Lévi-Strauss M, Pagani F, et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 2007; 448: 934–937.
- 31 Rowland LP, Hoefer PF, Aranow H, Merritt HH. Fatalities in myasthenia gravis: a review of 39 cases with 26 autopsies. Neurology 1958; 6: 310–326.
- 32 Mantegazza R, Beghi E, Pareyson D, Antozzi C, Peluchetti D, Sghirlanzoni A, et al. A multicentre follow-up study of 1152 patients with myasthenia gravis in Italy. J Neurol 1990; 237: 339–344.
- 33 Alshekhlee A, Miles JD, Katirji B, Preston DC, Kaminski HJ. Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology 2009; 72: 1548–1554.
- 34 Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity 2010; 43: 428–435.
- 35 Punga AR, Stålberg E. Acetylcholinesterase inhibitors in MG: to be or not to be? Muscle Nerve 2009; 39: 724–728.
- 36 Antozzi C, Gemma M, Regi B, Berta E, Confalonieri P, Peluchetti D, et al. A short plasma exchange protocol is effective in severe myasthenia gravis. J Neurol 1991; 238: 103–107.
- 37 Dalakas M. IVIg in other autoimmune neurological disorders: current status and future prospects. J Neurol 2008; 3: 12–16.
- 38 Antozzi C, Berta E, Confalonieri P, Zuffi M, Cornelio F, Mantegazza R. Protein-A immunoadsorption in immunosuppression-resistant myasthenia gravis. Lancet 1994; 343: 124.
- 39 Maddison P, McConville J, Farrugia ME, Davies N, Rose M, Norwood F, et al. The use of rituximab in myasthenia gravis and Lambert–Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry (in press).
- 40 Mantegazza R, Baggi F, Bernasconi P, Antozzi C, Confalonieri P, Novellino L, et al. Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of follow-up. J Neurol Sci 2003; 212: 31–36.
- 41 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: 444–448.
- 42 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: 536–538.
- 43 Müoller-Hermelink HK, Marx A, Geuder KI, Kirchner T. Thymus. In: I Damjanov, J Linder, editors. Anderson's pathology. Vol. I. St. Louis, MO: Mosby; 1996. p 1218–1243.
- 44 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: 726–738.
- 45 Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 2006; 6: 205–217.
- 46 Humby F, Bombardieri M, Manzo A, Kelly S, Blades MC, Kirkham B, et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med 2009; 6: e1
- 47 Armengol MP, Juan M, Lucas-Martín A, Fernández-Figueras MT, Jaraquemada D, Gallart T, et al. Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am J Pathol 2001; 159: 861–873.
- 48 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: 1935–1944.
- 49 Stott DI, Hiepe F, Hummel M, Steinhauser G, Berek C. Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjögren's syndrome. J Clin Invest 1998; 102: 938–946.
- 50 Zucherman NS, Howard WA, Bismuth J, Gibson K, Edelman H, Berrih-Aknin S, et al. Ectopic GC in the thymus of myasthenia gravis patients show characteristic of normal GC. Eur J Immunol 2010; 40: 1150–1161.
- 51 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: 185–197.
- 52 Wekerle H, Ketelsen UP. Intrathymic pathogenesis and dual genetic control of myasthenia gravis. Lancet 1977; 1: 678–680.
- 53 Schluep M, Willcox N, Vincent A, Dhoot GK, Newson-Davis J. Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study. Ann Neurol 1987; 22: 212–222.
- 54 Wakkach A, Poëa 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: 1229–1240.
- 55 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: 521–531.
- 56 Haynes BF, Hale LP. The human thymus. A chimeric organ comprised of central and peripheral lymphoid components. Immunol Res 1998; 18: 175–192.
- 57 Meraouna A, Cizeron-Clairac G, Le Panse R, Bismuth J, Truffault F, Tallaksen C, et al. The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. Blood 2006; 108: 432–440.
- 58 Tangarajh M, Masterman T, Helgeland L, Rot U, Jonsonn 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: 161–166.
- 59 Ragheb S, Lisak R, Lewis R, van Stavern G, Gonzales F, Simon K. A potential role for B-cell activating factor in the pathogenesis of autoimmune myasthenia gravis. Arch Neurol 2008; 65: 1358–1362.
- 60 Thorley-Lawson D. Epstein–Barr virus: exploiting the immune system. Nat Rev Immunol 2001; 1: 75–82.
- 61 Shiono H, Fujii Y, Okumura M, Takeuchi Y, Inoue M, Matsuda H. Failure to down-regulate Bcl-2 protein in thymic germinal center B cells in myasthenia gravis. Eur J Immunol 1997; 27: 805–809.
- 62 Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, et al. Induction of Bcl-2 expression by Epstein–Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 1991; 65: 1107–1115.
- 63 Masaoka A, Yamakama Y, Niwi H, Fukay I, Kondo S, Kobayashi M, et al. Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac Surg 1996; 62: 853–859.
- 64 Chen G, Marx A, Wen-Hu C, Yong J, Puppe B, Stroebel P, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002; 95: 420–429.
- 65 Okumura M, Shiono H, Minami M, Inoue M, Utsumi T, Kadota Y, et al. Clinical and pathological aspects of thymic epithelial tumors. Gen Thorac Cardiovasc Surg 2008; 56: 10–16.
- 66 Jaretzki A III, Penn AS, Younger DS. “Maximal” thymectomy for myasthenia gravis. Results. J Thorac Cardiovasc Surg 1988; 95: 747–757.
- 67 Berrih S, Morel E, Gaud C, Raimond F, Le Brigand H, Bach JF. Anti-AChR antibodies, thymic histology, and T cell subsets in myasthenia gravis. Neurology 1984; 34: 66–71.
- 68 Evoli A, Minisci C, Di Schino, Marsili F, Punzi C, Batocchi AP, et al. Thymoma in patients with MG: characteristic and long-term outcome. Neurology 2002; 59: 1844–1850.
- 69 Okumura M, Fujii Y, Shiono H, Inoue M, Minami M, Utsumi T, et al. Immunological function of thymoma and pathogenesis of paraneoplastic myasthenia gravis. Gen Thorac Cardiovasc Surg 2008; 56: 143–150.
- 70 Rosai J, Sobin LH. Histological typing of tumors of the thymus. In: World Health Organization. International histological classification of tumors, 2nd ed. New York: Springer; 1999. p 9–14.
- 71 Ströbel P, Bauer A, Puppe B, Ktaushaar T, Krein A, Toyka K, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol 2004; 22: 1501–1509.
- 72 Savino W, Manganella G, Verley JM, Wolff A, Berrih S, Levasseur P, et al. Thymoma epithelial cells secrete thymic hormone but do not express class II antigens of the major histocompatibility complex. J Clin Invest 1985; 76: 1140–1146.
- 73 Savino W, Berrih S, Dardenne M. Thymic epithelial antigen, acquired during ontogeny and defined by the anti-p19 monoclonal antibody, is lost in thymomas. Lab Invest 1984; 51: 292–296.
- 74 Fend F, Kirchner T, Marx A, Müller-Hermelink HK. B-cells in thymic epithelial tumours. An immunohistochemical analysis of intra- and extraepithelial B-cell compartments. Virchows Arch B Cell Pathol Incl Mod Pathol 1993; 63: 241–247.
- 75 Alexiev BA, Drachenberg CB, Burke AP. Thymomas: a cytological and immunohistochemical study, with emphasis on lymphoid and neuroendocrine markers. Diagn Pathol 2007; 2: 13–22.
- 76 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: 3752–3760.
- 77 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.
- 78 Sommer N, Willcox N, Harcourt GC, Newsom-Davis J. Myasthenic thymus and thymoma are selectively enriched in acetylcholine receptor specific T cells. Ann Neurol 1990; 28: 312–319.
- 79 Hill ME, Shiono H, Newsom-Davis J, Willcox N. The myasthenia gravis thymus: a rare source of human autoantibody-secreting plasma cells for testing potential therapeutics. J Neuroimmunol 2008; 201: 50–56.
- 80 Schönbeck S, Padberg F, Hohlfeld R, Wekerle H. Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis. J Clin Invest 1992; 90: 245–250.
- 81 Mesnard-Roullier L, Bismuth J, Wakkach A, Poëa-Guyon S, Berrih-Aknin S. Thymic myoid cells express high levels of muscle genes. J Neuroimmunol 2004; 148: 97–105.
- 82 Vincent A, Willcox N, Hill M, Curnow J, MacLennan C, Beeson D. Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis. Immunol Rev 1998; 164: 157–168.
- 83 Poëa-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: 5941–5949.
- 84 Kirchner T, Hoppc F, Schalke B, Müller-Hermelink HK. Microenvironment of thymic myoid cells in myasthenia gravis. Virchows Arch B Cell Pathol 1988; 54: 295–302.
- 85 Villadangos JA, Heath WR, Carbone FR. Outside looking in: the inner workings of the crosspresentation pathway within dendritic cells. Trends Immunol 2007; 28: 45–47.
- 86
Leite MI,
Jones M,
Ströbel 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:
893–905.
10.2353/ajpath.2007.070240 Google Scholar
- 87 Bornemann A, Kirchner T. Thymic myoid cell turnover in myasthenia gravis patients and in normal controls. Cell Tissue Res 1996; 284: 481–487.
- 88 Rosai J, Levine GD. Tumors of the thymus. In: Atlas of tumor pathology, series II. Fascicle 13. Washington, DC: Armed Forces Institute of Pathology; 1976. p 34–161.
- 89 MacLennan CA, Vincent A, Marx A, Willcox N, Gilhus NE, Newsom-Davis J, et al. Preferential expression of AChR ϵ-subunit in thymomas from patients with myasthenia gravis. J Neuroimmunol 2008; 201: 28–32.
- 90 Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol 2006; 24: 571–606.
- 91 Ruan QG, She JX. Autoimmune polyglandular syndrome type I and the autoimmune regulator. Clin Lab Med 2004; 24: 305–317.
- 92 Scarpino S, Di Napoli A, Stoppacciaro A, Antonelli M, Pilozzi E, Chiarle R, et al. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clin Exp Immunol 2007; 149: 504–512.
- 93 Hohlfeld R, Kalies I, Kohleisen B, Heininger K, Conti-Tronconi BM, Toyka KV. Myasthenia gravis: stimulation of antireceptor autoantibodies by autoreactive T cell lines. Neurology 1986; 36: 618–621.
- 94 Ahlberg R, Yi Q, Pirskanen R, Matell G, Swerup C, Rieber EP, et al. Treatment of myasthenia gravis with anti-CD4 antibody: improvement correlates to decreased T-cell autoreactivity. Neurology 1994; 44: 1732–1737.
- 95 Sommer N, Harcourt GC, Willcox N, Beason D, Newsom-Davis J. Acetylcholine receptor-reactive T lymphocytes from healthy subjects and myasthenia gravis patients. Neurology 1991; 41: 1270–1276.
- 96 Moiola L, Karachunski P, Protti MP, Howard JF, Conti-Tronconi BM. Epitopes on the beta subunit of human muscle acetylcholine receptor recognized by CD4+ cells of myasthenia gravis patients and healthy subjects. J Clin Invest 1994; 93: 1020–1028.
- 97 Levinson AI, Zheng Y, Gaulton G, Moore J, Pletcher CH, Song D, et al. A new model linking intra-thymic acetylcholine receptor expression and the pathogenesis of myasthenia gravis. Ann NY Acad Sci 2003; 998: 257–265.
- 98 Sisely A, Lisak RP, Brenner T. Proliferative response of blood cells of patients with myasthenia gravis to purified mammalian acetylcholine receptor. Pathol Immunopathol Res 1989; 8: 113–-117.
- 99 Protti MP, Manfredi AA, Straub C, Howard JF, Conti-Tronconi BM. Immunodominant regions for T helper-cell sensitization on the human nicotinic receptor alpha subunit in myasthenia gravis. Proc Natl Acad Sci 1990; 87: 7792–7796.
- 100 Ragheb S, Mohamed M, Lisak RP. Myasthenia gravis patients, but not healthy subjects, recognize epitopes that are unique to the ϵ-subunit of the acetylcholine receptor. J Neuroimmunol 2005; 159: 137–145.
- 101 Moulian N, Bidault J, Truffault F, Yamamoto AM, Levasseur P, Berrih-Aknin S. Thymocyte Fas expression is dysregulated in myasthenia gravis patients with anti-acetylcholine receptor antibody. Blood 1997; 89: 3287–3295.
- 102 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: 735–741.
- 103 Matsui N, Nakane S, Saito F, Ohigashi I, Nakagawa Y, Kurobe H, et al. Undiminished regulatory T cells in the thymus of patients with myasthenia gravis. Neurology 2010; 74: 816–820.
- 104 Luther C, Poeschel S, Varga M, Melms A, Tolosa E. Decreased frequency of intrathymic regulatory T cells in patients with myasthenia-associated thymoma. J Neuroimmunol 2005; 164: 124–128.
- 105 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 rat. Am J Pathol 1991; 139: 995–1008.
- 106 Le Panse R, Cizeron-Clairac G, Bismuth J, Berrih-Aknin S. 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 2006; 177: 7868–7879.
- 107 Guigou V, Emilie D, Berrih-Aknin S, Fumoux F, Fougereau M, Schiff C. Individual germinal centres of myasthenia gravis human thymuses contain polyclonal activated B cells that express all the VH and VK families. Clin Exp Immunol 1991; 83: 262–266.
- 108 Levinson AI, Zweiman B, Lisak RP. Pokeweed mitogen-induced immunoglobulin secretory responses of thymic B cells in myasthenia gravis: selective secretion of IgG versus IgM cannot be explained by helper functions of thymic T cells. Clin Immunol Immunopathol 1990; 57: 211–217.
- 109 Zeweiman B, Levinson AI, Lisak RP. Phenotypic characteristics of thymic B lymphocytes in myasthenia gravis. J Clin Immunol 1989; 9: 242–247.
- 110 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: 305–307.
- 111 Scadding GK, Vincent A, Newsom-Davis J, Henry K. Acetylcholine receptor antibody synthesis by thymic lymphocytes: correlation with thymic histology. Neurology 1981; 31: 935–943.
- 112 Willcox HN, Newsom-Davis J, Calder LR. Greatly increased autoantibody production in myasthenia gravis by thymocyte suspensions prepared with proteolytic enzymes. Clin Exp Immunol 1983; 54: 378–386.
- 113 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: 604–608.
- 114 Lisak RP, Laramore C, Levinson AI, Zewiman B, Moskovitz AR, Witte A. In vitro synthesis of antibodies to acetylcholine receptor by peripheral blood cells: role of suppressor T cells in normal subjects. Neurology 1984; 34: 802–805.
- 115 Lisak RP, Laramore C, Levinson AI, Zweiman B, Moskovitz AR. Suppressor T cells in myasthenia gravis and antibodies to acetylcholine receptor. Ann Neurol 1986; 19: 87–89.
- 116
Padberg F,
Matsuda M,
Fenk R,
Patenge N,
Kubuschok B,
Hohlfeld R, et al.
Myasthenia gravis: selective enrichment of anti-acetylcholine receptor antibody production in untransformed human B cell cultures.
Eur J Immunol
1999;
29:
3538–3548.
10.1002/(SICI)1521-4141(199911)29:11<3538::AID-IMMU3538>3.0.CO;2-Y CAS PubMed Web of Science® Google Scholar
- 117 Fujii Y, Hashimoto J, Monden Y, Ito T, Nakahara K, Kawashima Y. Specific activation of lymphocytes against acetylcholine receptor in the thymus in myasthenia gravis. J Immunol 1986; 136: 887–891.
- 118 Safar D, Berrih-Aknin S, Morel E. In vitro anti-acetylcholine receptor antibody synthesis by myasthenia gravis patient lymphocytes: correlations with thymic histology and thymic epithelial cell interaction. J Clin Immunol 1987; 7: 225–234.
- 119 Newsom-Davis J, Willcox N, Calder L. Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes. N Engl J Med 1981; 305: 1313–1318.
- 120 Lisak RP, Levinson AI, Zweiman B, Kornstein MJ. Antibodies to acetylcholine receptor and tetanus toxoid: in vitro synthesis by thymic lymphocytes. J Immunol 1986; 137: 1221–1225.
- 121 Leprince C, Cohen-Kaminsky S, Berrih-Aknin S, Vernet-Der Garabedian B, Treton D, Galanaud P, et al. Thymic B cells from myasthenia gravis patients are activated B cells. Phenotypic and functional analysis. J Immunol 1990; 145: 2115–2122.
- 122 Berzi A, Ayata CK, Cavalcante P, Falcone C, Candiago E, Motta T, et al. BDNF and its receptors in human myasthenic thymus: implications for cell fate in thymic pathology. J Neuroimmunol 2008; 197: 128–139.
- 123 Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J Exp Med 2007; 204: 2899–2912.
- 124 Beghi E, Antozzi C, Batocchi AP, Cornelio F, Cosi V, Evoli A. Prognosis of myasthenia gravis: a multi center follow-up study of 844 patients. J Neurol Sci 1991; 106: 213–220.
- 125 Sonett JR, Jaretzki A III. Thymectomy for nonthymomatous myasthenia gravis. A critical analysis. Ann NY Acad Sci 2008; 1132: 315–328.
- 126 Okumura M, Ohta M, Takeuchi Y, Shiono H, Inoue M, Fukuhara K, et al. The immunological role of thymectomy in the treatment of myasthenia gravis: implication of thymus-associated B-lymphocyte subset in reduction of the anti-acetylcholine receptor antibody titer. J Thorac Cardiovasc Surg 2003; 126: 1922–1928.
- 127 Mori T, Nomori H, Ikeda K, Kobayashi H, Iwatani K, Kobayashi T. The distribution of parenchyma, follicles, and lymphocyte subsets in thymus of patients with myasthenia gravis, with special reference to remission after thymectomy. J Thorac Cardiovasc Surg 2007; 133: 364–368.
- 128 Fujii Y, Monden Y, Hashimoto J, Nakahara K, Kawashima Y. Acetylcholine receptor antibody-producing cells in thymus and lymph nodes in myasthenia gravis. Clin Immunol Immunopathol 1985; 34: 141–146.
- 129 Novellino L, Longoni M, Spinelli L, Andretta M, Cozzi M, Faillace G. ‘Extended’ thymectomy without sternotomy performed by cervicotomy and thoracoscopic technique in the treatment of myasthenia gravis. Int Surg 1994; 79: 378–381.
- 130 Goldstein SD, Yang SC. Assessment of robotic thymectomy using the myasthenia gravis Foundation of America guidelines. Ann Thorac Surg 2010; 89: 1080–1086.
- 131 Bachmann K, Burkhardt D, Schreiter I, Kaifi J, Schurr P, Busch C, et al. Thymectomy is more effective than conservative treatment for myasthenia gravis regarding outcome and clinical improvement. Surgery 2009; 145: 392–398.
- 132 Jaretzki A III, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al. Myasthenia gravis. Recommendations for clinical research standards. Neurology 2000; 55: 16–23.
- 133 Okumura M, Inoue M, Kadota Y, Hayashi A, Tokunaga T, Kusu T, et al. Biological implications of thymectomy for myasthenia gravis. Surg Today 2010; 40: 102–107.
- 134 Shi F-D, Ljunggren H-G, Sarvetnick N. Innate immunity and autoimmunity: from self-protection to self-destruction. Trends Immunol 2001; 22: 97–101.
- 135 Crampton SP, Voynova E, Bolland S. Innate pathways to B cell activation and tolerance. Ann NY Acad Sci 2010; 1183: 58–68.
- 136 Feferman T, Maiti PK, Berrih-Aknin S, Bismuth J, Bidault J, Fuchs S, et al. Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis. J Immunol 2005; 174: 5324–5331.
- 137 Cohen-Kaminsky S, Devergne O, Delattre RM, Klingel-Schmitt I, Emilie D, Galanaud P, et al. Interleukin-6 overproduction by cultured thymic epithelial cells from patients with myasthenia gravis is potentially involved in thymic hyperplasia. Eur Cytokine Netw 1993; 4: 121–132.
- 138 Colombara M, Antonini V, Riviera AP, Mainiero F, Strippoli R, Merola M, et al. Constitutive activation of p38 and ERK1/2 MAPKs in epithelial cells of myasthenic thymus leads to IL-6 and RANTES overexpression: effects on survival and migration of peripheral T and B cells. J Immunol 2005; 175: 7021–7028.
- 139 Cizeron-Clairac G, Le Panse R, Frenkian-Cuvelier M, Meraouna A, Truffault F, Bismuth J, et al. Thymus and myasthenia gravis: what can we learn from DNA microarrays?. J Neuroimmunol 2008; 201: 57–63.
- 140 Münz C, Lünemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol 2009; 9: 246–257.
- 141 Niller HH, Wolf H, Minarovits J. Regulation and dysregulation of Epstein–Barr virus latency: implications for the development of autoimmune diseases. Autoimmunity 2008; 41: 298–328.
- 142 Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11: 373–384.
- 143 Di Rosa F, Barnaba V. Persisting viruses and chronic inflammation: understanding their relationship to autoimmunity. Immunol Rev 1998; 164: 17–27.
- 144 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: 1271–1275.
- 145 Korn IL, Abramsky O. Myasthenia gravis following viral infection. Eur Neurol 1981; 20: 435–439.
- 146 Bhibhatbhan A, Kline G, Vincent A, Toth C. Anti-MuSK myasthenia gravis presenting with Epstein–Barr virus-associated mononucleosis and immune-mediated diabetes mellitus. Muscle Nerve 2007; 36: 264–266.
- 147 Verma A, Berger J. Myasthenia gravis associated with dual infection of HIV and HTLV-I. Muscle Nerve 1995; 18: 1355–1356.
- 148 Schwimmbeck PL, Dyrberg T, Drachman DB, Oldstone MBA. Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor alpha-subunit that has biologic activity and reacts immunochemically with herpes simplex virus. J Clin Invest 1989; 84: 1174–1180.
- 149 Stefansson K, Dieperink ME, Richman DP, Gomez CM, Marton LS. Sharing of antigenic determinants between the nicotinic acetylcholine receptor and proteins in Escherichia coli, Proteus vulgaris, and Klebsiella pneumoniae. Possible role in the pathogenesis of myasthenia gravis. N Engl J Med 1985; 312: 221–225.
- 150 Klavinskis LS, Willcox N, Newsom-Davis J. Antivirus antibodies in myasthenia gravis. Neurology 1985; 35: 1381–1384.
- 151 Tindall RSA, Cloud R, Lucky J, Rosenberg RN. Serum antibodies to cytomegalovirus in myasthenia gravis: effects of thymectomy and steroids. Neurology 1978; 28: 273–277.
- 152 Aoki T, Drachman DB, Asher DM, Gibbs CJ, Bahmanyar S, Wolinsky JS. Attempts to implicate viruses in myasthenia gravis. Neurology 1985; 35: 185–192.
- 153 Klavinski LS, Willcox HNA, Richmond JE, Newsom-Davis J. Attempted isolation of viruses from myasthenia gravis thymus. J Neuroimmunol 1986; 11: 287–299.
- 154 McGuire LJ, Huang DP, Teoh R, Arnold M, Wong L, Lee JC. Epstein–Barr virus genome in thymoma and thymic lymphoid hyperplasia. Am J Pathol 1988; 131: 385–390.
- 155 Manca N, Perandin F, De Simone N, Giannini F, Bonifati D, Angelini C. Detection of HTLV-I tax-rex and pol gene sequences of thymus gland in large group of patients with myasthenia gravis. J Acquir Immune Defic Syndr 2002; 29: 300–306.
- 156 Bernasconi P, Barberis M, Baggi F, Passerini L, Cannone M, Arnoldi E, et al. Increased Toll-like receptor 4 expression in thymus of myasthenia gravis patients. Am J Pathol 2005; 167: 129–139.
- 157 Cavalcante P, Barberis M, Cannone M, Baggi F, Antozzi C, Maggi L, et al. Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis. Neurology 2010; 74: 1118–1126.
- 158 Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, et al. Epstein–Barr virus infection is not characteristic feature of multiple sclerosis brain. Brain 2009; 132: 3318–3328.
- 159 Peferoen LAN, Lamers F, Lodder LNR, Gerritsen WH, Huitinga I, Melief J, et al. Epstein–Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain 2010; 133: e137.
- 160 Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, et al. Absence of Epstein–Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 2010; 74: 1127–1135.
- 161 Aloisi F, Serafini B, Magliozzi R, Howell OW, Reynolds R. Detection of Epstein–Barr virus and B-cell follicles in the multiple sclerosis brain: what you find depends on how and where you look. Brain 2010; 133: e157.
- 162 Kaminski HJ, Minarovits J. Epstein–Barr virus: trigger for autoimmunity? Ann Neurol 2010; 67: 697–698.
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