General Thoracic and Cardiovascular Surgery

, Volume 56, Issue 4, pp 143–150 | Cite as

Immunological function of thymoma and pathogenesis of paraneoplastic myasthenia gravis

  • Meinoshin Okumura
  • Yoshitaka Fujii
  • Hiroyuki Shiono
  • Masayoshi Inoue
  • Masato Minami
  • Tomoki Utsumi
  • Yoshihisa Kadota
  • Yoshiki Sawa
Current Topics Review Article


Thymoma and thymic carcinoma are the representative tumors arising from the thymic epithelium. Thymoma is well known for association with autoimmune diseases including myasthenia gravis, suggesting its biological activity. Herein, recent progress in research of thymoma is reviewed with reference to its immunological function. Myasthenia gravis is frequently associated with WHO type B1 and B2 thymomas. These types of thymomas hold a significant number of CD4+CD8+ double-positive T cells, and at the same time, the neoplastic epithelial cells express HLA-DR molecules at a slightly reduced level compared with the normal thymus. The impaired expression of HLA-DR molecules in neoplastic epithelial cells of thymomas possibly affects positive selection of CD4+CD8 single-positive T cells and may result in alteration of its repertoire. The function of thymoma neoplastic cells as the cortical epithelium of the thymus and the morphological resemblance of thymomas to the cortex suggest that thymoma is of cortical epithelial origin; this might imply that thymoma lacks the functional medulla where professional antigenpresenting cells are engaged in negative selection. These findings suggest that thymoma generates autoreactive T cells causing autoimmunity. Further investigation on immunological function of thymoma is supposed to elucidate the pathogenesis of thymoma-related autoimmunity and the high affinity of thymoma with myasthenia gravis. In addition, studying the biology of thymoma is also expected to contribute to further understanding of T-cell development and immunological tolerance in the human, because thymoma can be considered an acquired thymus.

Key words

Thymoma Thymic carcinoma T-cell development Human leukocyte antigen Paraneoplastic autoimmunity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rosai J, Sobin LH. Histological typing of tumours of the thymus. International histological classification of tumours. 2nd ed. New York: Springer; 1999.Google Scholar
  2. 2.
    World Health Organization Classification of Tumors. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: International Agency for Research on Cancer (IARC) Press; 2004.Google Scholar
  3. 3.
    Vincent A. Immunology of acetylcholine receptors in relation to myasthenia gravis. Physiol Rev 1980;60:756–824.PubMedGoogle Scholar
  4. 4.
    Lindstrom J, Shelton D, Fujii Y. Myasthenia gravis. Adv Immunol 1988;42:233–284.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    Okumura M, Ohta M, Takeuchi Y, Shiono H, Inoue M, Fukuhara K, et al. The immunologic role of thymectomy in the treatment of myasthenia gravis. Implication of thymusassociated B lymphocyte subset in reduction of the anti-acetylcholine receptor antibody titer. J Thorac Cardiovasc Surg 2003;126:1922–1928.PubMedCrossRefGoogle Scholar
  7. 7.
    Adkins B, Mueller C, Okada CY, Reichert RA, Weissman IL, Spangrude GJ. Early events in T-cell maturation. Annu Rev Immunol 1987;5:325–365.PubMedCrossRefGoogle Scholar
  8. 8.
    Sprent J. T lymphocytes and the thymus. Fundamental immunology. 3rd ed. New York: Raven Press; 1993. p 75–109.Google Scholar
  9. 9.
    Scollay R, Wilson A, D’Amico A, Kelly K, Egerton M, Pearse M, et al. Developmental status and reconstitution potential of subpopulations of murine thymocytes. Immunol Rev 1988;104:81–120.PubMedCrossRefGoogle Scholar
  10. 10.
    Shortman K, Egerton M, Spangrude GJ, Scollay R. The generation and fate of thymocytes. Semin Immunol 1990;2:3–12.PubMedGoogle Scholar
  11. 11.
    Alvarez-Vallina L, Gonzalez A, Gambon F, Kreisler M, Diaz-Espada F. Delimitation of the proliferative stages in the human thymus indicates that cell expansion occurs before the expression of CD3. J Immunol 1993;150:8–16.PubMedGoogle Scholar
  12. 12.
    Takeuchi Y, Fujii Y, Okumura M, Inada K, Nakahara K, Matsuda H. Characterization of CD4+ single positive cells that lack CD3 in the human thymus. Cell Immunol 1993;151:481–490.PubMedCrossRefGoogle Scholar
  13. 13.
    Lauriola L, Maggiano N, Marino M, Carbone A, Piantelli M, Musiani P. Human thymoma: immunologic characteristics of the lymphocytic component. Cancer (Phila) 1981;48:1992–1995.CrossRefGoogle Scholar
  14. 14.
    Aisenberg AC, Wilkes B, Harris NL, Frist WH. The predominant lymphocyte in most thymomas and in nonneoplastic thymus from patients with myasthenia gravis is the cortical thymocyte. Clin Immunol Immunopathol 1985;35:130–136.PubMedCrossRefGoogle Scholar
  15. 15.
    Fujii Y, Hayakawa M, Nakahara K. Thymus cells in myasthenia gravis: a two-colour fl ow cytometric analysis of lymphocytes in the thymus and thymoma. J Neurol 1992;239:82–88.PubMedCrossRefGoogle Scholar
  16. 16.
    Inoue M, Okumura M, Fujii Y, Miyoshi S, Shiono H, Fukuhara K, et al. Immaturity of lymphocytes in the metastatic lesions of thymoma. Clin Immunol Immunopathol 1998;88:249–255.PubMedCrossRefGoogle Scholar
  17. 17.
    Okumura M, Fujii Y, Miyoshi S, Shiono H, Inoue M, Kadota Y, et al. 3-color fl ow cytometric study on lymphocytes derived from thymic diseases. J Surg Res 2001;101:130–137.PubMedCrossRefGoogle Scholar
  18. 18.
    Müller-Hermelink HK, Wilisch A, Schultz A, Marx A. Characterization of the human thymic microenvironment: lymphoepithelial interaction in mormal thymus and thymoma. Arch Histol Cytol 1997;60:9–28.PubMedCrossRefGoogle Scholar
  19. 19.
    Inoue M, Fujii Y, Okumura M, Takeuchi Y, Shiono H, Miyoshi S, et al. Neoplastic thymic epithelial cells of human thymoma support T cell development from CD4CD8 cells to CD4+CD8+ cells in vivo. Clin Exp Immunol 1998;112:419–426.PubMedCrossRefGoogle Scholar
  20. 20.
    Okumura M, Miyoshi S, Fujii Y, Takeuchi Y, Shiono H, Inoue M, et al. Clinical and functional significance of WHO classification on human thymic epithelial neoplasms. A study of 146 consecutive tumors. Am J Surg Pathol 2001;25:103–110.PubMedCrossRefGoogle Scholar
  21. 21.
    Inoue M, Fujii Y, Okumura M, Takeuchi Y, Shiono H, Miyoshi S, et al. Mature CD4 single positive thymocytes in human thymoma: T cells may differentiate in the thymic epithelial cell tumor. Pathobiology 1997;65:216–222.PubMedGoogle Scholar
  22. 22.
    Stroebel P, Helmreich M, Menioudakis G, Lewin SR, Ruediger T, Bauer A, et al. Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood 2002;100:159–166.CrossRefGoogle Scholar
  23. 23.
    Buckley C, Douek D, Newsome-Davis J, Vincent A, Willcox N. Mature, long-lived CD4+ and CD8+ T cell are generated by thy thymoma in myasthenia gravis. Ann Neurol 2001;50:64–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Takeuchi Y, Fujii Y, Okumura M, Inada K, Nakahara K, Matsuda H. Accumulation of immature CD3CD4+CD8 single-positive cells that lack CD69 in epithelial cell tumors of the human thymus. Cell Immunol 1995;161:181–187.PubMedCrossRefGoogle Scholar
  25. 25.
    Inada K, Okumura M, Shiono H, Inoue M, Kadota Y, Ohta M, et al. A role of positive selection of thymoma-associated T cells in the pathogenesis of myasthenia gravis. J Surg Res 2005;126:34–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Inoue M, Okumura M, Miyoshi S, Shiono H, Fukuhara K, Kadota Y, et al. Impaired expression of MHC class II molecules in response to interferon-gamma (IFN-γ) on human thymoma neoplastic epithelial cells. Clin Exp Immunol 1999;117:1–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Bach B, Steimle V, Martinez-Soria E, Reith W. Regulation of MHC class II genes: lessons from a disease. Annu Rev Immunol 1996;14:301–331.CrossRefGoogle Scholar
  28. 28.
    Kadota Y, Okumura M, Miyoshi S, Kitagawa-Sakakida S, Inoue M, Shiono H, et al. Altered T cell development in human thymoma is related to impairment of MHC class II transactivator expression induced by interferon-gamma (IFN-γ). Clin Exp Immunol 2000;121:59–68.PubMedCrossRefGoogle Scholar
  29. 29.
    Ashton-Rickardt PG, Tonegawa S. A differential avidity model for T-cell selection. Immunol Today 1994;15:362–366.PubMedCrossRefGoogle Scholar
  30. 30.
    Hogquist KA, Jameson SC, Bevan MJ. The ligand for positive selection of T lymphocytes in the thymus. Curr Opin Immunol 1994;6:273–278.PubMedCrossRefGoogle Scholar
  31. 31.
    Meager A, Vincent A, Newsom-Davis J, Willcox N. Spontaneous neutralizing antibodies to interferon-alpha and interleukin-12 in thymoma-associated autoimmune disease. Lancet 1997;350:1596.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Association for Thoracic Surgery 2008

Authors and Affiliations

  • Meinoshin Okumura
    • 1
  • Yoshitaka Fujii
    • 2
  • Hiroyuki Shiono
    • 1
  • Masayoshi Inoue
    • 1
  • Masato Minami
    • 1
  • Tomoki Utsumi
    • 1
  • Yoshihisa Kadota
    • 1
  • Yoshiki Sawa
    • 1
  1. 1.Department of General Thoracic Surgery (L5)Osaka University Graduate School of MedicineOsakaJapan
  2. 2.Department of Surgery IINagoya City University Medical SchoolNagoyaJapan

Personalised recommendations